Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid malignancies with very few therapeutic options to treat advanced or metastatic disease. The utilization of genomic sequencing has identified therapeutically relevant alterations in approximately 25% of PDAC patients, most notably in the DNA damage response and repair (DDR) genes, rendering cancer cells more sensitive to DNA-damaging agents and to DNA damage response inhibitors, such as PARP inhibitors. ATM is one of the most commonly mutated DDR genes, with somatic mutations identified in 2% to 18% of PDACs and germline mutations identified in 1% to 34% of PDACs. ATM plays a complex role as a cell-cycle checkpoint kinase, regulator of a wide array of downstream proteins, and responder to DNA damage for genome stability. The disruption of ATM signaling leads to downstream reliance on ATR and CHK1, among other DNA-repair mechanisms, which may enable exploiting the inhibition of downstream proteins as therapeutic targets in ATM-mutated PDACs. In this review, we detail the function of ATM, review the current data on ATM deficiency in PDAC, examine the therapeutic implications of ATM alterations, and explore the current clinical trials surrounding the ATM pathway.

This article is featured in Highlights of This Issue, p. 1897

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid malignancies with fewer than 10% of patients surviving 5 years. Disease incidence is increasing, and PDAC is projected to be the second most common cause of cancer-related death by 2030 (1, 2). The high mortality is due to the majority of patients presenting with locally advanced or metastatic disease at the time of diagnosis. Unfortunately, despite recent improvements in outcomes with newer chemotherapy regimens, the median survival remains less than 1 year (3, 4). Comprehensive genetic analysis is being pursued to identify mutational pathways for potential treatment options, and a recent study utilizing genomic sequencing identified therapeutically relevant (highly actionable) alterations in 27% of PDAC samples (5). These findings were consistent with several other publications, all of which have demonstrated findings of actionable targets in 17% to 48% of PDAC samples (6–11). One commonality to these large-scale next-generation sequencing efforts is the identification of mutational defects in the genes that regulate the DNA damage response and repair (DDR) system, found in 17% to 25% of PDACs.

During the cell cycle, there is a replication of over 6 billion base pairs of DNA. Such genomic replication is subject to numerous insults and replication stressors, which rely on essential response and repair mechanisms to ensure DNA's integrity. Furthermore, the chemotherapies used to treat cancers, particularly pancreatic cancer, result in specific types of DNA damage. For example, alkylating agents, such as platinums, and topoisomerase inhibitors, such as irinotecan, cause double-strand DNA breaks (DSB), whereas antimetabolites such as 5-fluorouracil and gemcitabine cause singe base-pair damage that can lead to single-strand DNA breaks (12). Deficiencies in DDR mechanisms have revealed targets for therapy, and research has led to FDA-approved treatments targeting cancers that harbor such deficiencies. For example, BRCA1 and BRCA2 play an integral role in the maintenance of genomic integrity, and germline mutations in either gene lead to increased risks for breast, ovarian, pancreatic, and prostate cancers (13). However, the presence of a BRCA1/2 mutation also predicts for an improved response and improved overall survival with platinum-based chemotherapy in both triple-negative breast cancers and PDAC (14, 15). Exploiting this DNA-repair defect not only improves sensitivity to chemotherapy, but also allows targetable therapy through the inhibition of the poly [adenosine diphosphate (ADP)–ribose] polymerase (PARP), leading to the accumulation of single-strand breaks which compromise DNA double-strand integrity at the replication fork. PARP inhibitors increase progression-free survival in advanced BRCA1/2-mutated ovarian and breast cancer (16–18), and are now FDA approved for these diseases. Additionally, responses to PARP inhibitors are also frequently seen in BRCA-mutated castrate-resistant prostate cancer with, for example, a response rate of 88% in a 50-patient trial; and in BRCA-mutated pancreatic cancer, with responses of 16% to 22% in small trials of 19 and 23 patients, respectively (16, 19–21).

ATM also plays a critical role in DDR. The ataxia telangiectasia mutated (ATM) gene, located on chromosome 11q 22–23, was first identified in 1995 during the evaluation of the ataxia telangiectasia syndrome. Germline mutations of ATM result in a well-characterized syndrome, as well as an increased predisposition for breast, pancreatic, and prostate cancers (22–28). Relevant here, mutations in the ATM gene, whether germline or somatic, are found in up to ∼6% of PDACs (further details below), and thus may represent a more prevalent DDR mutation than BRCA1/2 (7). In this review, we detail the function of ATM, review the current data on ATM deficiency in PDACs, and examine the therapeutic implications of ATM alterations.

The ATM gene consists of 66 exons that encode a PI3K-related serine/threonine protein kinase that plays a central role in the response to, and ultimately the repair of DNA DSB. Structurally, this large protein (350 kDa) contains serine or threonine residues susceptible for phosphorylation, followed by a glutamine amino acid located near its hydrophobic target region. Similar sites for posttranslational modifications (PTM) are found in the ataxia telangiectasia and RAD 3-related (ATR) kinase and in the DNA protein kinase (DNA-PK) proteins (29). ATM has important functions in the cell, including the maintenance of (i) telomere length (30, 31) and (ii) the mitotic spindle structure during mitosis (32). However, this review solely focuses on the central role of ATM in the process of DDR, including as it relates to targeted therapies in cancer. As depicted in Fig. 1, in order to repair damaged DNA, the MRE11-RAD50-NBS1 (MRN) complex acts as the primary sensor for DSBs and creates a physical bridge between the two broken ends (33). ATM can then interact directly with NBS1 (part of the MRN complex) through the direct binding of the C-terminus of NBS1 to several of the HEAT repeats that reside in ATM (34). It is believed that several PTMs are required for subsequent ATM activation. For instance, ATM has been shown to be activated through acetylation of K3016 by TIP60, a histone acetyltransferase that binds to ATM through recognition of the C-terminal FATC domain (35). ATM also requires autophosphorylation at S1981, which allows the kinase domain to dissociate from the FAT domain, enabling, in turn, the kinase to become active (36). These modifications allow ATM to transition from an inactive homodimer into an active monomer in response to DNA damage (36). This mechanism has been supported in the literature, but also questioned by others, demonstrating the need for further work in the field to clearly identify the role of S1981 and other ATM autophosphorylation events (29, 36, 37). Once activated, ATM phosphorylates multiple substrates, protein kinases, and sensor proteins in order to carry out DSB repair and also regulate normal cell-cycle processes, such as apoptosis and checkpoint activation (36, 38, 39).

Figure 1.

ATM functions and other related pathways for DNA repair. ATM is recruited to DSBs by the MRN complex through direct interaction of NSB1 with ATM's HEAT repeats. ATM is then activated through autophosphorylation, and acetylation by TIP60; this activation allows ATM to dissociate to the active monomeric state. ATM monomers can then signal for DNA repair through BRCA1 and γ-H2AX. ATM can also signal for cell-cycle arrest and/or apoptosis through the activation of p53 through direct phosphorylation and indirect activation through CHK2 and MDM2. In parallel, ATR is recruited to long stretches of single-strand DNA caused by single-strand breaks, the resection of DSBs, or replication stress. PARP1 is another factor that is critical for the repair of single-strand breaks.

Figure 1.

ATM functions and other related pathways for DNA repair. ATM is recruited to DSBs by the MRN complex through direct interaction of NSB1 with ATM's HEAT repeats. ATM is then activated through autophosphorylation, and acetylation by TIP60; this activation allows ATM to dissociate to the active monomeric state. ATM monomers can then signal for DNA repair through BRCA1 and γ-H2AX. ATM can also signal for cell-cycle arrest and/or apoptosis through the activation of p53 through direct phosphorylation and indirect activation through CHK2 and MDM2. In parallel, ATR is recruited to long stretches of single-strand DNA caused by single-strand breaks, the resection of DSBs, or replication stress. PARP1 is another factor that is critical for the repair of single-strand breaks.

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ATM plays a role in the signaling required to initiate DNA repair, and thus, ATM defects can lead to genomic instability and malignancy. Hereditary and sporadic ATM mutations span the functional domains of the entire ATM gene (Fig. 2). These mutations occur mostly in the C-terminal end, which interacts with the PI3 kinase domain. This domain is involved with acetylation and activation of ATM (40). DDR is impaired when the ATM protein is dysfunctional, and loss of this DDR mechanism designed for DSBs can possibly lead, over time, to the accumulation of mutations, which can, in theory initiate the process of tumorigenesis. For instance, germline point mutations in ATM result in increased risks of breast cancers, specifically those associated with the S49C and S707P mutations. Melanoma, prostate, and oropharyngeal cancers are specifically associated with the S49C mutation. Although thyroid or endocrine cancers are generally associated with the S707P mutation (41, 42). Next-generation sequencing has also revealed somatic ATM mutations in many tumor types, including PDAC (Fig. 2; ref. 40).

Figure 2.

ATM structure–function domains and frequent mutations in PDAC. ATM has several important domains that are critical for ATM function as either a monomer, dimer, or both. The TAN domain is critical for telomerase function and recruitment to DSBs. This recruitment is also dependent on interactions between the ATM HEAT repeats and NBS1 (part of the MRN complex; refs. 31, 34). The FAT domain normally inhibits the kinase activity as a dimer, but after DNA damage induced autophosphorylation at S1981 and subsequent dissociation of the dimer the kinase domain becomes active (36). The FATC domain is critical for interaction with TIP60, and TIP60 acetylation of ATM at K3016 is necessary for ATM activation. Mutational analysis of PDAC patients with ATM mutations from Cbio-portal (date of accession January 21, 2019) did not show significant clustering or hotspot mutations in ATM, but the number of patients was low (N = 34).

Figure 2.

ATM structure–function domains and frequent mutations in PDAC. ATM has several important domains that are critical for ATM function as either a monomer, dimer, or both. The TAN domain is critical for telomerase function and recruitment to DSBs. This recruitment is also dependent on interactions between the ATM HEAT repeats and NBS1 (part of the MRN complex; refs. 31, 34). The FAT domain normally inhibits the kinase activity as a dimer, but after DNA damage induced autophosphorylation at S1981 and subsequent dissociation of the dimer the kinase domain becomes active (36). The FATC domain is critical for interaction with TIP60, and TIP60 acetylation of ATM at K3016 is necessary for ATM activation. Mutational analysis of PDAC patients with ATM mutations from Cbio-portal (date of accession January 21, 2019) did not show significant clustering or hotspot mutations in ATM, but the number of patients was low (N = 34).

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Multiple studies have reaffirmed the importance of TP53, KRAS, CDKN2A, and SMAD4 mutations in PDAC (7, 11, 43, 44). Inherited risks of PDAC are also well established to be in large part due to germline mutations in BRCA1/BRCA2 and CDKN2A, identified in 7.4% of familial pancreatic cancers (N = 727; ref. 45), as well as individuals affected by Lynch syndrome (mutations in the genes: MLH1, MSH2, PMS2, and MSH6; ref. 46). Additionally, a study of familial PDAC patients showed that deleterious ATM mutations were significantly higher than the control group, suggesting ATM's role in malignancy (25). This knowledge has led to germline and somatic mutations in ATM as being identified and added to the catalog of predisposing gene mutations.

A genomic characterization of PDAC revealed 37% of the 71 samples carried alterations in DNA-repair genes (6). This significant discovery has also been confirmed in a recent large PDAC profiling study that identified targetable alterations in 50% of 640 PDAC patients, of which 8.4% expressed BRCA1/2 or ATM mutations (5). A review of the International Cancer Genome Consortium, a large database of sporadic PDACs, in 2015 identified ATM mutations in 9% to 18% of PDACs, with an average of 12% of the 591 samples (47). An additional large population study that identified the prevalence of homologous recombination–related gene mutations in 15.4% of PDACs (48). This study also revealed that ATM, ATRX, and CHEK2 mutations are present in 1.3% of 50,000 tumor samples. These mutations were most prevalently identified in PDAC (48). Further genomic studies support the high prevalence of ATM, CHEK2, and ATR mutations in PDAC (8). Our literature search, capturing 5,234 pancreatic cancer patients overall, shows that the total prevalence of ATM mutations (germline or somatic) in PDAC is 6.4% (range, 1%–34%; refs. 5, 6, 8, 9, 11, 25, 47–57). Importantly, in one study that showed that nearly 10% of PDAC patients carried a germline ATM mutation, in 44% of these patients a somatic second hit was identified (58). Although this loss-of-heterozygosity (LOH) seems to occur frequently in tumors arising from patients with germline ATM mutations (e.g., as seen in breast and pancreatic cancers; refs. 59, 60), the necessity of LOH to confer therapeutic sensitivity (i.e., to platinums and DDR inhibitors, as discussed below) is uncertain.

It is now well established that tumor cells with underlying defects in DDR are exquisitely sensitive to DNA-damaging agents, notably platinums, and more recently to PARP inhibitors in a phenomenon known as synthetic lethality (61). Similarly, inactivating mutations in ATM can also set up synthetic lethality in the presence of DNA-damaging agents (62). Historically, ataxia telangiectasia patients were found to be profoundly radiosensitive at the chromosomal level, suggesting the link between ATM and DNA repair (63). Preclinical data have demonstrated that knockdown of ATM results in radiosensitization (64, 65). Additional studies in the laboratory have demonstrated that ATM alterations in malignant cells can sensitize cells to platinum drugs (44, 66), and outside of platinum therapy, preclinical studies have also demonstrated ATM suppression in p53-deficient mouse fibroblasts sensitizes them to doxorubicin (67). Previous work has also demonstrated that ATM deficiency in p53-deficient cell lines causes a modest increase in 5-FU sensitivity (68). Lastly, one study took advantage of ATM-mutated PDAC cells in a mouse model and showed that treatment with the PARP inhibitor olaparib or the ATR inhibitor VE-822 led to dramatic accumulation of DSBs and reduced tumor cell viability in vitro and in vivo (62). The authors noted the compensation of alternate signaling routes to bypass ATM deficiency, including ATR in the replicative stress response. Thus, ATR inhibition was efficient in promoting intolerable mitotic damage, an effect that was enhanced when combined with gemcitabine (62).

The clinical experience in PDAC patients with confirmed ATM, ATR, or CHEK2 mutations is very limited, and focused on the efficacy of oxaliplatin-based chemotherapy. One case series (N = 71) utilizing real-time whole-exome sequencing demonstrated that a majority of patients with such mutations experienced a partial response or stable disease with oxaliplatin-based chemotherapy (6). In this case series, 80% of those with ATM, ATR, or CHEK2 mutations were treated with an oxaliplatin-based chemotherapy and 62.5% demonstrated partial response or stable disease on first follow-up scans (6). Another small study (N = 13) demonstrated a 37.5% response rate to oxaliplatin-based chemotherapy regimens in patients with DDR-mutated tumors (69). There was also a significantly longer progression-free survival compared with those patients whose tumors were DDR-nonmutated (20.8 months vs. 1.7 months, respectively P = 0.049; ref. 69). Specifically, 4 of 30 patients had known pathogenic ATM mutations, with at least one patient experiencing a prolonged partial response of nearly 40 months on 5-FU, irinotecan, and oxaliplatin (FOLFIRINOX; ref. 69). There are currently multiple ongoing trials targeting ATM-deficient tumors, including and especially with PARP inhibitors (Table 1).

Table 1.

ATM-relevant trials

DDR targetDrug nameNCT identifierPhaseStudy sizeATM status consideredStudy title (pancreatic cancer eligible trials are in bold)
ATM AZD0156 NCT02588105 83 No Study to Assess the Safety and Preliminary Efficacy of AZD0156 at Increasing Doses Alone or in Combination with Other Anticancer Treatment in Patients with Advanced Cancer (AToM) 
 AZD1390 NCT03423628 132 No A Study to Assess the Safety and Tolerability of AZD1390 Given with Radiation Therapy in Patients with Brain Cancer 
ATR M6620 (VX-970) NCT02723864 60 No Veliparib (ABT-888), an Oral PARP Inhibitor, and VX-970, an ATR Inhibitor, in Combination with Cisplatin in People with Refractory Solid Tumors 
 M6620 (VX-970) NCT02595931 51 No VX-970 and Irinotecan Hydrochloride in Treating Patients with Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery 
 M6620 (VX-970) NCT03641313 II 28 Exploratory objective ATR Kinase Inhibitor M6620 and Irinotecan in Treating Patients with Progressive, Metastatic, or Unresectable TP53-Mutant Gastric or Gastroesophageal Junction Cancer 
 M6620 (VX-970) NCT03517969 II 130 No ATR Kinase Inhibitor VX-970 and Carboplatin with or without Docetaxel in Treating Participants with Metastatic Castration-Resistant Prostate Cancer 
 M6620 (VX-970) NCT02567409 II 90 No Cisplatin and Gemcitabine Hydrochloride with or without ATR Kinase Inhibitor M6620 in Treating Patients with Metastatic Urothelial Cancer 
 M6620 (VX-970) NCT02595892 II 70 No Gemcitabine Hydrochloride Alone or with M6620 in Treating Patients with Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer 
 M6620 (VX-970) NCT02627443 111 No Carboplatin and Gemcitabine Hydrochloride with or without ATR Kinase Inhibitor VX-970 in Treating Patients with Recurrent and Metastatic Ovarian, Primary Peritoneal, or Fallopian Tube Cancer 
 M6620 (VX-970) NCT02487095 I/II 70 No Trial of Topotecan with VX-970, an ATR Kinase Inhibitor, in Small Cell Cancers and Extrapulmonary Small Cell Cancers 
 M6620 (VX-970) NCT03641547 65 No M6620 plus Standard Treatment in Oesophageal and Other Cancer (CHARIOT) 
 M6620 (VX-970) NCT02567422 45 No M6620, Cisplatin, and Radiation Therapy in Treating Patients with Locally Advanced HPV-Negative Head and Neck Squamous Cell Carcinoma 
 M6620 (VX-970) NCT02589522 46 No VX-970 and Whole Brain Radiation Therapy in Treating Patients with Brain Metastases from Non–small Cell Lung Cancer, Small Cell Lung Cancer, or Neuroendocrine Tumors 
 M6620 (VX-970) NCT03718091 II 223 Yes M6620 (VX-970) in Selected Solid Tumors 
 AZD6738 NCT03682289 II 68 No Phase II Trial of AZD6738 Alone and in Combination with Olaparib 
 AZD6738 NCT03462342 II 86 No Combination ATR and PARP Inhibitor (CAPRI) Trial with AZD6738 and Olaparib in Recurrent Ovarian Cancer (CAPRI) 
 AZD6738 NCT03787680 II 47 No Targeting Resistant Prostate Cancer with ATR and PARP Inhibition (TRAP Trial) 
 AZD6738 NCT03328273 I/II 62 No A Study of AZD6738 and Acalabrutinib in Subjects with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) 
 AZD6738 NCT03669601 50 No AZD6738 and Gemcitabine as Combination Therapy (ATRiUM) 
 AZD6738 NCT03770429 Ib 52 No AZD6738 for Patients with Progressive MDS or CMML 
 AZD6738 NCT02264678 250 Yes Ascending Doses of AZD6738 in Combination with Chemotherapy and/or Novel Anticancer Agents 
 BAY1895344 NCT03188965 219 Yes First-in-human Study of ATR Inhibitor BAY1895344 in Patients with Advanced Solid Tumors and Lymphomas 
CHK1/2 Prexasertib NCT02873975 II 50 Yes A Study of LY2606368 (Prexasertib) in Patients with Solid Tumors with Replicative Stress or Homologous Repair Deficiency 
 Prexasertib NCT03057145 24 No Combination Study of Prexasertib and Olaparib in Patients with Advanced Solid Tumors 
 Prexasertib NCT03495323 28 No A Study of Prexasertib (LY2606368), CHK1 Inhibitor, and LY3300054, PD-L1 Inhibitor, in Patients with Advanced Solid Tumors 
 Prexasertib NCT02203513 II 153 No A Phase II Single-Arm Pilot Study of the Chk1/2 Inhibitor (LY2606368) in BRCA1/2 Mutation-Associated Breast or Ovarian Cancer, Triple-Negative Breast Cancer, High-Grade Serous Ovarian Cancer, and Metastatic Castrate-Resistant Prostate Cancer 
 Prexasertib NCT02808650 65 No Prexasertib in Treating Pediatric Patients with Recurrent or Refractory Solid Tumors 
 Prexasertib NCT03735446 28 No Prexasertib in Combination with MEC in Relapsed/Refractory AML and High-Risk MDS – A Phase I Trial 
 SRA737 NCT02797964 I/II 170 Chk1 or ATR or other related gene A Phase 1/2 Trial of SRA737 in Subjects with Advanced Cancer 
 SRA737 NCT02797977 I/II 140 Yes A Phase 1/2 Trial of SRA737 in Combination with Gemcitabine plus Cisplatin or Gemcitabine Alone in Subjects with Advanced Cancer 
Additional Trials Targeting ATM-Deficient Tumors 
PARP Olaparib NCT02576444 II 64 No OLAParib COmbinations (OLAPCO) 
 Olaparib NCT03842228 Ib 102 Yes Copanlisib, Olaparib, and Durvalumab in Treating Patients with Metastatic or Unresectable Solid Tumors 
 Olaprib NCT03009682 II 28 Yes Olaparib Monotherapy in Relapsed Small Cell Lung Cancer Patients with HR Pathway Gene Mutations Not Limited to BRCA 1/2 Mutations, ATM Deficiency or MRE11A Mutations (SUKSES-B) 
 Olaparib NCT03012321 II 70 Yes Abiraterone/Prednisone, Olaparib, or Abiraterone/Prednisone + Olaparib in Patients with Metastatic Castration-Resistant Prostate Cancer with DNA-Repair Defects 
 Olaparib NCT03786796 II 20 Yes Study of Olaparib in Metastatic Renal Cell Carcinoma Patients with DNA-Repair Gene Mutations (ORCHID) 
 Olaparib NCT03570476 Pilot 15 Yes Olaparib Before Surgery in Treating Participants with Localized Prostate Cancer 
 Olaparib NCT03375307 II 60 Yes Olaparib in Treating Patients with Metastatic or Advanced Urothelial Cancer with DNA-Repair Defects 
 Olaparib NCT02734004 I/II 427 No A Phase I/II Study of MEDI4736 in Combination with Olaparib in Patients with Advanced Solid Tumors (MEDIOLA) 
 Talozaparib NCT03565991 II 200 Yes Javelin BRCA/ATM: Avelumab plus Talazoparib in Patients with BRCA or ATM-Mutant Solid Tumors 
 Talozaparib NCT02286687 II 150 Yes Study of the PARP Inhibitor BMN 673 in Advanced Cancer Patients with Somatic Alterations in BRCA1/2, Mutations/Deletions in PTEN or PTEN Loss, a Homologous Recombination Defect, Mutations/Deletions in Other BRCA Pathway Genes and Germline Mutation in BRCA1/2 (Not Breast or Ovarian Cancer) 
 Talozaparib NCT03330405 Ib/2 242 No Javelin Parp Medley: Avelumab plus Talazoparib In Locally Advanced or Metastatic Solid Tumors 
 Talozaparib NCT03377556 II 64 Yes Lung-MAP: Talazoparib in Treating Patients with HRRD Positive Recurrent Stage IV Squamous Cell Lung Cancer 
 Talozparib NCT02401347 II 58 Yes Phase II Talazoparib in BRCA1 + BRCA2 Wild-Type and Triple-Neg/HER2-Negative Breast Cancer/Solid Tumors 
 Niraparib NCT03209401 146 Yes Niraparib plus Carboplatin in Patients with Homologous Recombination Deficient Advanced Solid Tumor Malignancies 
 Niraparib NCT03207347 II 47 Yes A Trial of Niraparib in BAP1 and Other DNA Damage Response (DDR) Deficient Neoplasms (UF-STO-ETI-001) 
 Rucaparib NCT02952534 II 360 Yes A Study of Rucaparib in Patients with Metastatic Castration-resistant Prostate Cancer and Homologous Recombination Gene Deficiency (TRITON2) 
DDR targetDrug nameNCT identifierPhaseStudy sizeATM status consideredStudy title (pancreatic cancer eligible trials are in bold)
ATM AZD0156 NCT02588105 83 No Study to Assess the Safety and Preliminary Efficacy of AZD0156 at Increasing Doses Alone or in Combination with Other Anticancer Treatment in Patients with Advanced Cancer (AToM) 
 AZD1390 NCT03423628 132 No A Study to Assess the Safety and Tolerability of AZD1390 Given with Radiation Therapy in Patients with Brain Cancer 
ATR M6620 (VX-970) NCT02723864 60 No Veliparib (ABT-888), an Oral PARP Inhibitor, and VX-970, an ATR Inhibitor, in Combination with Cisplatin in People with Refractory Solid Tumors 
 M6620 (VX-970) NCT02595931 51 No VX-970 and Irinotecan Hydrochloride in Treating Patients with Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery 
 M6620 (VX-970) NCT03641313 II 28 Exploratory objective ATR Kinase Inhibitor M6620 and Irinotecan in Treating Patients with Progressive, Metastatic, or Unresectable TP53-Mutant Gastric or Gastroesophageal Junction Cancer 
 M6620 (VX-970) NCT03517969 II 130 No ATR Kinase Inhibitor VX-970 and Carboplatin with or without Docetaxel in Treating Participants with Metastatic Castration-Resistant Prostate Cancer 
 M6620 (VX-970) NCT02567409 II 90 No Cisplatin and Gemcitabine Hydrochloride with or without ATR Kinase Inhibitor M6620 in Treating Patients with Metastatic Urothelial Cancer 
 M6620 (VX-970) NCT02595892 II 70 No Gemcitabine Hydrochloride Alone or with M6620 in Treating Patients with Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer 
 M6620 (VX-970) NCT02627443 111 No Carboplatin and Gemcitabine Hydrochloride with or without ATR Kinase Inhibitor VX-970 in Treating Patients with Recurrent and Metastatic Ovarian, Primary Peritoneal, or Fallopian Tube Cancer 
 M6620 (VX-970) NCT02487095 I/II 70 No Trial of Topotecan with VX-970, an ATR Kinase Inhibitor, in Small Cell Cancers and Extrapulmonary Small Cell Cancers 
 M6620 (VX-970) NCT03641547 65 No M6620 plus Standard Treatment in Oesophageal and Other Cancer (CHARIOT) 
 M6620 (VX-970) NCT02567422 45 No M6620, Cisplatin, and Radiation Therapy in Treating Patients with Locally Advanced HPV-Negative Head and Neck Squamous Cell Carcinoma 
 M6620 (VX-970) NCT02589522 46 No VX-970 and Whole Brain Radiation Therapy in Treating Patients with Brain Metastases from Non–small Cell Lung Cancer, Small Cell Lung Cancer, or Neuroendocrine Tumors 
 M6620 (VX-970) NCT03718091 II 223 Yes M6620 (VX-970) in Selected Solid Tumors 
 AZD6738 NCT03682289 II 68 No Phase II Trial of AZD6738 Alone and in Combination with Olaparib 
 AZD6738 NCT03462342 II 86 No Combination ATR and PARP Inhibitor (CAPRI) Trial with AZD6738 and Olaparib in Recurrent Ovarian Cancer (CAPRI) 
 AZD6738 NCT03787680 II 47 No Targeting Resistant Prostate Cancer with ATR and PARP Inhibition (TRAP Trial) 
 AZD6738 NCT03328273 I/II 62 No A Study of AZD6738 and Acalabrutinib in Subjects with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) 
 AZD6738 NCT03669601 50 No AZD6738 and Gemcitabine as Combination Therapy (ATRiUM) 
 AZD6738 NCT03770429 Ib 52 No AZD6738 for Patients with Progressive MDS or CMML 
 AZD6738 NCT02264678 250 Yes Ascending Doses of AZD6738 in Combination with Chemotherapy and/or Novel Anticancer Agents 
 BAY1895344 NCT03188965 219 Yes First-in-human Study of ATR Inhibitor BAY1895344 in Patients with Advanced Solid Tumors and Lymphomas 
CHK1/2 Prexasertib NCT02873975 II 50 Yes A Study of LY2606368 (Prexasertib) in Patients with Solid Tumors with Replicative Stress or Homologous Repair Deficiency 
 Prexasertib NCT03057145 24 No Combination Study of Prexasertib and Olaparib in Patients with Advanced Solid Tumors 
 Prexasertib NCT03495323 28 No A Study of Prexasertib (LY2606368), CHK1 Inhibitor, and LY3300054, PD-L1 Inhibitor, in Patients with Advanced Solid Tumors 
 Prexasertib NCT02203513 II 153 No A Phase II Single-Arm Pilot Study of the Chk1/2 Inhibitor (LY2606368) in BRCA1/2 Mutation-Associated Breast or Ovarian Cancer, Triple-Negative Breast Cancer, High-Grade Serous Ovarian Cancer, and Metastatic Castrate-Resistant Prostate Cancer 
 Prexasertib NCT02808650 65 No Prexasertib in Treating Pediatric Patients with Recurrent or Refractory Solid Tumors 
 Prexasertib NCT03735446 28 No Prexasertib in Combination with MEC in Relapsed/Refractory AML and High-Risk MDS – A Phase I Trial 
 SRA737 NCT02797964 I/II 170 Chk1 or ATR or other related gene A Phase 1/2 Trial of SRA737 in Subjects with Advanced Cancer 
 SRA737 NCT02797977 I/II 140 Yes A Phase 1/2 Trial of SRA737 in Combination with Gemcitabine plus Cisplatin or Gemcitabine Alone in Subjects with Advanced Cancer 
Additional Trials Targeting ATM-Deficient Tumors 
PARP Olaparib NCT02576444 II 64 No OLAParib COmbinations (OLAPCO) 
 Olaparib NCT03842228 Ib 102 Yes Copanlisib, Olaparib, and Durvalumab in Treating Patients with Metastatic or Unresectable Solid Tumors 
 Olaprib NCT03009682 II 28 Yes Olaparib Monotherapy in Relapsed Small Cell Lung Cancer Patients with HR Pathway Gene Mutations Not Limited to BRCA 1/2 Mutations, ATM Deficiency or MRE11A Mutations (SUKSES-B) 
 Olaparib NCT03012321 II 70 Yes Abiraterone/Prednisone, Olaparib, or Abiraterone/Prednisone + Olaparib in Patients with Metastatic Castration-Resistant Prostate Cancer with DNA-Repair Defects 
 Olaparib NCT03786796 II 20 Yes Study of Olaparib in Metastatic Renal Cell Carcinoma Patients with DNA-Repair Gene Mutations (ORCHID) 
 Olaparib NCT03570476 Pilot 15 Yes Olaparib Before Surgery in Treating Participants with Localized Prostate Cancer 
 Olaparib NCT03375307 II 60 Yes Olaparib in Treating Patients with Metastatic or Advanced Urothelial Cancer with DNA-Repair Defects 
 Olaparib NCT02734004 I/II 427 No A Phase I/II Study of MEDI4736 in Combination with Olaparib in Patients with Advanced Solid Tumors (MEDIOLA) 
 Talozaparib NCT03565991 II 200 Yes Javelin BRCA/ATM: Avelumab plus Talazoparib in Patients with BRCA or ATM-Mutant Solid Tumors 
 Talozaparib NCT02286687 II 150 Yes Study of the PARP Inhibitor BMN 673 in Advanced Cancer Patients with Somatic Alterations in BRCA1/2, Mutations/Deletions in PTEN or PTEN Loss, a Homologous Recombination Defect, Mutations/Deletions in Other BRCA Pathway Genes and Germline Mutation in BRCA1/2 (Not Breast or Ovarian Cancer) 
 Talozaparib NCT03330405 Ib/2 242 No Javelin Parp Medley: Avelumab plus Talazoparib In Locally Advanced or Metastatic Solid Tumors 
 Talozaparib NCT03377556 II 64 Yes Lung-MAP: Talazoparib in Treating Patients with HRRD Positive Recurrent Stage IV Squamous Cell Lung Cancer 
 Talozparib NCT02401347 II 58 Yes Phase II Talazoparib in BRCA1 + BRCA2 Wild-Type and Triple-Neg/HER2-Negative Breast Cancer/Solid Tumors 
 Niraparib NCT03209401 146 Yes Niraparib plus Carboplatin in Patients with Homologous Recombination Deficient Advanced Solid Tumor Malignancies 
 Niraparib NCT03207347 II 47 Yes A Trial of Niraparib in BAP1 and Other DNA Damage Response (DDR) Deficient Neoplasms (UF-STO-ETI-001) 
 Rucaparib NCT02952534 II 360 Yes A Study of Rucaparib in Patients with Metastatic Castration-resistant Prostate Cancer and Homologous Recombination Gene Deficiency (TRITON2) 

NOTE: The table summarizes currently open clinical trials that directly or indirectly target ATM-deficient tumors. The trials were captured from a search on clinicaltrials.gov on March 2, 2019. Clinical trials that potentially accept pancreatic cancer patients are shown in bold.

Because ATM, ATR, and CHK1 are all important for resolving DNA damage (Fig. 1), utilizing an underlying DDR defect and inducing synthetic lethality by inhibiting an additional kinase is an innovative way to induce cancer cell death. The use of small-molecule inhibitors of ATM, ATR, and CHK1 is a promising avenue of cancer treatment due to the malignant cells' rapid and unregulated cell division. There are currently phase I and II clinical trials utilizing ATM or ATR inhibitors as monotherapy as well as in combination with chemotherapy (70, 71).

ATM inhibitors

The first compound described to inhibit ATM was wortmannin (72); however, there are now a host of newer, more potent compounds that inhibit ATM. One of the newer generation of ATM inhibitors published in 2004 was KU55933. This compound was shown to inhibit downstream ATM phosphorylation after radiation, and it also enhanced responses to the topoisomerase inhibitors etoposide, camptothecins, and doxorubicin (73). A similar sensitization to topoisomerase inhibitors was later demonstrated with the ATM inhibitor AZ31, which was shown to increase the efficacy of irinotecan in resistant tumors in PDX models (74). KU60019 is another compound that was introduced in 2009 as an improved analogue of KU55933 (75), and early work demonstrated that KU60019 is a potent radiosensitizer (75). This molecule is currently being studied in in clear-cell renal cell carcinoma in combination with another known sensitizing agent, CX4945, which is an inhibitor of the protein kinase CK2 (76). The rationale for this combination comes from a compound screen where CK2 and ATM inhibitors were found to be highly synergistic in renal cancer. Interestingly, when CK2 inhibitors were tested in isogenic ATM-proficient and -deficient mouse cell lines, there was little difference in downstream effectors of DNA repair, such as AKT1 and BID, although overall viability in the ATM proficient and deficient cell lines treated with CK2 inhibitors was not assessed (77). This brings to light an important point when comparing the efficacy of interventions performed in combination with ATM inhibitors, as compared with these same interventions performed in patients with ATM-deficient tumors. The results may potentially be divergent as tumors with constitutive deficiency in ATM may have adapted to chronic loss of ATM function as opposed to acute loss as induced by ATM inhibitors. Conversely, other interventions may be both synergistic with ATM inhibitors and more potent in ATM-deficient patients.

Beyond the preclinical explorations of ATM inhibitors, currently two ATM inhibitors in clinical trials are being investigated in combination with other therapies (Table 1). AZD0156, an oral ATM inhibitor, is currently in clinical trials in combination with olaparib or FOLFIRI (78). These combinations are rational because, as previously mentioned, ATM inhibitors have been shown to sensitize cells to PARP inhibitors, and also to both 5-FU and irinotecan (61, 62, 68). AZD1390, another oral ATM inhibitor that penetrates the blood–brain barrier, is currently being tested in combination with radiation, given that radiation has been demonstrated to be more effective in ATM-deficient cancers (65, 79, 80). Importantly, in considering the potential adverse events for this trial, knockout of ATM in healthy tissue as compared with cancerous tissue was shown to induce less radiation sensitivity (80). This work demonstrated that increased sensitivity to radiation through ATM inhibition was primarily seen in cells that were rapidly replicating. As ATM inhibitors are further explored in the clinic, it will, of course, be important to monitor the side effects of ATM inhibitors particularly in combination with other therapies.

Increased sensitivity of ATM-deficient tumors to PARP inhibitors has previously been shown (64, 75, 81), and in a clinical trial of 124 patients, it has been demonstrated that dosing with olaparib and paclitaxel was more effective at increasing overall survival in patients with less ATM activity (HR, 0.35; 80% CI, 0.22–0.56; P = 0.002; median OS, not reached vs. 8.2 months; ref. 82). Unfortunately, the subsequent phase III trial with 525 patients did not enrich for patients with ATM-deficient tumors and was a negative study (83). Nevertheless, there are multiple ongoing trials of PARP inhibitor–based therapy targeting patients, at least in part, with ATM-deficient tumors (Table 1).

ATR inhibitors

ATR is a phosphoinositide 3-kinase-related protein kinase that primarily responds to and repairs single-strand DNA breaks. It also shares functional sequences with ATM and DNA-PK, which respond to DSBs (29, 76). Upstream protein phosphorylation by ATM and autophosphorylation at the T1989 site stimulates ATR activity as well as TopBP1, which contains an ATR-activation domain to stimulate the kinase's activity (29, 84). The ATR kinase responds to a wide array of cell stressors, maintains DNA's integrity during replication, and is essential for proliferating cell survival. In the rapidly dividing cancer cell, there exists a high degree of replicative stress, creating an environment in which, as preclinical research has shown, suppression of ATR activity further increases replication stress leading to cell death (84). Furthermore, although normal dividing cells utilize ATM-dependent pathways for assistance in DNA repair, cancer cells, which are often deficient in ATM/p53 signaling, may rely solely on the ATR pathway for survival (67, 85, 86). This was demonstrated in genetically engineered mouse models of cancer, in which 90% genetic reduction of ATR expression suppressed the development of fibrosarcomas and acute myeloid leukemias with minimal side effects in normal tissues. This work affirmed the tumor selectivity of ATR inhibition (84). Moreover, inhibition of ATR selectively sensitizes tumor cells, but not normal cells, to radiation and chemotherapy (87).

Thus, small-molecule inhibitors of ATR may be particularly potent in PDACs with somatic mutations in ATM given that the lack of ATM's function may lead to increased dependence on ATR, and ATR inhibition could thus significantly promote cancer cell death. The ATR inhibitor VE-821 sensitizes cancer cells but not normal cells to chemotherapy (87), and these effects were synergistic in ATM-deficient cells (87). Another ATR inhibitor, AZD6738, causes accumulation of DNA damage, S phase arrest, and apoptosis in ATM dysfunctional gastric cells while not affecting those with functional ATM (88). Similar preclinical studies also suggest synthetic lethality between ATR inhibition with VE-822 and ATM deficiency in PDAC as well as lung adenocarcinoma cell lines, reaffirming the actionable molecular dependencies on ATR (62, 81). VE-822 has also been shown to potentially synergize with cisplatin in ATM-deficient esophageal squamous cells (89). This effect of potentiating the cytotoxicity of cisplatin and gemcitabine is also seen with AZD6738 in ATM-deficient non–small cell lung cancer cells (90). Several ongoing trials of ATR inhibitor-based therapies are listed in Table 1.

CHK1 and CHK2 inhibitors

Downstream to and activated by ATR is the checkpoint kinase 1 (CHK1) pathway. CHK1 promotes proteasomal degradation of CDC25A in response to genome stress (29). The combined activity of ATR, CHK1, and CDC25A results in cell-cycle arrest and stabilization of replication stress at DNA forks. The inhibition of this complex leads to a decreased rate of fork progression, massive fork collapse in S phase cells, and ultimately cell death (82). Preclinical studies utilizing the CHK1 inhibitors MK8776 and LY2603618, with gemcitabine-based chemoradiation, showed synergistic effects to induce apoptosis of PDAC cells (91, 92). The combination of gemcitabine, a CHK1 inhibitor, PF-477736, and Lutetium-177–labeled anti-EGFR antibody leads to extensive DNA damage, apoptosis, and tumor degeneration in patient-derived xenografts (93). Additional preclinical studies with a tumor stem cell marker Doublecortin-like kinase 1 (Dclk1) inhibitor, LRRK2-IN-1 (LRRK), showed decreased expression of phosphorylated Chk1 (94). This same study demonstrated the combination of gemcitabine with LRRK significantly reduced cell survival compared with treatment with gemcitabine alone (94). Thus, CHK1 and Dclk1 are both potential targets in ATM-deficient malignancies as they also play a large role in single-strand break DNA repair.

CHK1 activation is primarily dependent on ATR at stalled replication forks and single-strand DNA, whereas CHK2 is activated mainly by ATM induced by DNA DSBs. One preclinical study examined the antitumor effects of a CHK2 inhibitor, NSC109555, in combination with gemcitabine. This combination increased apoptosis in pancreatic cells (95). Clinical trials of CHK1/2 inhibitors are also listed in Table 1.

There are currently no FDA-approved targeted therapies for patients with pancreatic cancer. However, genomic profiling of pancreatic adenocarcinomas is revealing therapeutically relevant alterations, and 17% to 25% of pancreatic cancers harbor mutations in the DDR pathway. Therapy targeted toward inhibiting the DNA damage response, including with PARP inhibitors, is proving to be highly effective particularly in DDR-deficient cancers, as has been established in BRCA1/2 mutated cancers. However, DDR is a highly complicated process, involving several overlapping pathways. It is reasonable to hypothesize that, depending upon the specific DDR mutation, there may be different optimal therapies to be utilized. PARP inhibitors are showing early promise in PDACs that harbor BRCA1/2 or PALB2 mutations, but consistently the most common DDR gene mutated in PDAC is actually ATM. It will be critical in the coming years to explore what DDR-targeted therapies might work best in ATM-deficient tumors. As with any therapeutic breakthrough, the future exploration of the complexity of the DDR pathway also justifies the need for a better understanding of compensatory and resistance mechanisms that may arise in the setting of ATM/ATR/CHK1–targeted therapies.

ATM deficiency may provide sensitivity for other elements of conventional therapies for PDAC, including radiation (96) and oxaliplatin. However, emerging targeted strategies, including immunotherapeutic combination approaches (97), will likely provide even better matches for ATM-deficient tumors. For example, mechanistically, it seems reasonable to consider that PARP inhibitors may be effective in treating ATM-deficient tumors. But potentially more promising might be the combination of a PARP inhibitor with an ATR inhibitor in ATM-deficient PDAC—essentially exploiting a new node of synthetic lethality in the DDR pathway. Similarly, there is a mechanistic reason to explore the role of CHK1 inhibition in ATM-deficient tumors. In both cases, understanding the need for inducing DNA damage with DNA-damaging chemotherapy will be critical as well. There are several ongoing clinical trials as discussed above, but clinical trials in PDAC in which there is such a high unmet need, and where ATM deficiency is common, would be ideal.

Additionally, recent genetic studies have revealed that specific ATM genotypes correlate to susceptibility to different diseases including cancer, which may provide valuable clinical information with regard to early detection, the subtyping of, and the treatment of PDACs (98). These genetic studies may complement and/or be evaluated in published genetically engineered mouse models (47, 62, 99) that have identified ATM's various roles (i.e., EMT, genetic instability, and metastases) in the progression model of PDAC. Moving forward, the research community should evaluate novel agents and combination therapies discussed above in these isogenic, in vivo models with the ultimate aim of classifying each ATM pathogenic genotype observed in patients with an optimally tailored, matched targeted therapeutic strategy.

No potential conflicts of interest were disclosed.

J.R. Brody and M.J. Pishvaian are supported by an NIH–NCI R01 CA212600 grant, and J.R. Brody is also supported by an NIH–NCI P30CA056036 core grant given to K. Knudsen. Research is supported by the 2015 Pancreatic Cancer Action Network–AACR Research Acceleration Network Grant, grant number 15-90-25-BROD, to J.R. Brody and M.J. Pishvaian.

1.
Quante
AS
,
Ming
C
,
Rottmann
M
,
Engel
J
,
Boeck
S
,
Heinemann
V
, et al
Projections of cancer incidence and cancer-related deaths in Germany by 2020 and 2030
.
Cancer Med
2016
;
5
:
2649
56
.
2.
Rahib
L
,
Smith
BD
,
Aizenberg
R
,
Rosenzweig
AB
,
Fleshman
JM
,
Matrisian
LM
. 
Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States
.
Cancer Res
2014
;
74
:
2913
21
.
3.
Conroy
T
,
Desseigne
F
,
Ychou
M
,
Bouche
O
,
Guimbaud
R
,
Becouarn
Y
, et al
FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer
.
N Engl J Med
2011
;
364
:
1817
25
.
4.
Von Hoff
DD
,
Ervin
T
,
Arena
FP
,
Chiorean
EG
,
Infante
J
,
Moore
M
, et al
Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine
.
N Engl J Med
2013
;
369
:
1691
703
.
5.
Pishvaian
MJ
,
Bender
RJ
,
Halverson
D
,
Rahib
L
,
Hendifar
AE
,
Mikhail
S
, et al
Molecular profiling of patients with pancreatic cancer: initial results from the Know Your Tumor initiative
.
Clin Cancer Res
2018
;
24
:
5018
27
.
6.
Aguirre
AJ
,
Nowak
JA
,
Camarda
ND
,
Moffitt
RA
,
Ghazani
AA
,
Hazar-Rethinam
M
, et al
Real-time genomic characterization of advanced pancreatic cancer to enable precision medicine
.
Cancer Discov
2018
;
8
:
1096
111
.
7.
Bailey
P
,
Chang
DK
,
Nones
K
,
Johns
AL
,
Patch
AM
,
Gingras
MC
, et al
Genomic analyses identify molecular subtypes of pancreatic cancer
.
Nature
2016
;
531
:
47
52
.
8.
Witkiewicz
AK
,
McMillan
EA
,
Balaji
U
,
Baek
G
,
Lin
WC
,
Mansour
J
, et al
Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets
.
Nat Commun
2015
;
6
:
6744
.
9.
Lowery
MA
,
Jordan
EJ
,
Basturk
O
,
Ptashkin
RN
,
Zehir
A
,
Berger
MF
, et al
Real-time genomic profiling of pancreatic ductal adenocarcinoma: potential actionability and correlation with clinical phenotype
.
Clin Cancer Res
2017
;
23
:
6094
100
.
10.
Moffitt
RA
,
Marayati
R
,
Flate
EL
,
Volmar
KE
,
Loeza
SG
,
Hoadley
KA
, et al
Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma
.
Nat Genet
2015
;
47
:
1168
78
.
11.
Biankin
AV
,
Waddell
N
,
Kassahn
KS
,
Gingras
MC
,
Muthuswamy
LB
,
Johns
AL
, et al
Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes
.
Nature
2012
;
491
:
399
405
.
12.
Helleday
T
,
Petermann
E
,
Lundin
C
,
Hodgson
B
,
Sharma
RA
. 
DNA repair pathways as targets for cancer therapy
.
Nat Rev Cancer
2008
;
8
:
193
204
.
13.
Chen
CC
,
Feng
W
,
Lim
PX
,
Kass
EM
,
Jasin
M
. 
Homology-directed repair and the role of BRCA1, BRCA2, and related proteins in genome integrity and cancer
.
Annu Rev Cancer Biol
2018
;
2
:
313
36
.
14.
Tutt
A
,
Tovey
H
,
Cheang
MCU
,
Kernaghan
S
,
Kilburn
L
,
Gazinska
P
, et al
Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT trial
.
Nat Med
2018
;
24
:
628
37
.
15.
Golan
T
,
Kanji
ZS
,
Epelbaum
R
,
Devaud
N
,
Dagan
E
,
Holter
S
, et al
Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers
.
Br J Cancer
2014
;
111
:
1132
8
.
16.
Kaufman
B
,
Shapira-Frommer
R
,
Schmutzler
RK
,
Audeh
MW
,
Friedlander
M
,
Balmana
J
, et al
Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation
.
J Clin Oncol
2015
;
33
:
244
50
.
17.
Robson
M
,
Im
SA
,
Senkus
E
,
Xu
B
,
Domchek
SM
,
Masuda
N
, et al
Olaparib for metastatic breast cancer in patients with a germline BRCA mutation
.
N Engl J Med
2017
;
377
:
523
33
.
18.
Litton
JK
,
Rugo
HS
,
Ettl
J
,
Hurvitz
SA
,
Goncalves
A
,
Lee
KH
, et al
Talazoparib in patients with advanced breast cancer and a germline BRCA mutation
.
N Engl J Med
2018
;
379
:
753
63
.
19.
Mateo
J
,
Carreira
S
,
Sandhu
S
,
Miranda
S
,
Mossop
H
,
Perez-Lopez
R
, et al
DNA-repair defects and olaparib in metastatic prostate cancer
.
N Engl J Med
2015
;
373
:
1697
708
.
20.
Domchek
SM
,
Aghajanian
C
,
Shapira-Frommer
R
,
Schmutzler
RK
,
Audeh
MW
,
Friedlander
M
, et al
Efficacy and safety of olaparib monotherapy in germline BRCA1/2 mutation carriers with advanced ovarian cancer and three or more lines of prior therapy
.
Gynecol Oncol
2016
;
140
:
199
203
.
21.
Shroff
RT
,
Hendifar
A
,
McWilliams
RR
,
Geva
R
,
Epelbaum
R
,
Rolfe
L
, et al
Rucaparib monotherapy in patients with pancreatic cancer and a known deleterious BRCA mutation
.
JCO Precis Oncol
2018
;
2018
. doi:
10.1200/PO.17.00316
.
22.
Savitsky
K
,
Bar-Shira
A
,
Gilad
S
,
Rotman
G
,
Ziv
Y
,
Vanagaite
L
, et al
A single ataxia telangiectasia gene with a product similar to PI-3 kinase
.
Science
1995
;
268
:
1749
53
.
23.
Antoniou
AC
,
Easton
DF
. 
Models of genetic susceptibility to breast cancer
.
Oncogene
2006
;
25
:
5898
905
.
24.
Cavaciuti
E
,
Lauge
A
,
Janin
N
,
Ossian
K
,
Hall
J
,
Stoppa-Lyonnet
D
, et al
Cancer risk according to type and location of ATM mutation in ataxia-telangiectasia families
.
Genes Chromosomes Cancer
2005
;
42
:
1
9
.
25.
Roberts
NJ
,
Jiao
Y
,
Yu
J
,
Kopelovich
L
,
Petersen
GM
,
Bondy
ML
, et al
ATM mutations in patients with hereditary pancreatic cancer
.
Cancer Discov
2012
;
2
:
41
6
.
26.
Grant
RC
,
Al-Sukhni
W
,
Borgida
AE
,
Holter
S
,
Kanji
ZS
,
McPherson
T
, et al
Exome sequencing identifies nonsegregating nonsense ATM and PALB2 variants in familial pancreatic cancer
.
Hum Genomics
2013
;
7
:
11
.
27.
Pritchard
CC
,
Mateo
J
,
Walsh
MF
,
De Sarkar
N
,
Abida
W
,
Beltran
H
, et al
Inherited DNA-repair gene mutations in men with metastatic prostate cancer
.
N Engl J Med
2016
;
375
:
443
53
.
28.
Angele
S
,
Falconer
A
,
Edwards
SM
,
Dork
T
,
Bremer
M
,
Moullan
N
, et al
ATM polymorphisms as risk factors for prostate cancer development
.
Br J Cancer
2004
;
91
:
783
7
.
29.
Blackford
AN
,
Jackson
SP
. 
ATM, ATR, and DNA-PK: the trinity at the heart of the DNA damage response
.
Mol Cell
2017
;
66
:
801
17
.
30.
Lee
SS
,
Bohrson
C
,
Pike
AM
,
Wheelan
SJ
,
Greider
CW
. 
ATM kinase is required for telomere elongation in mouse and human cells
.
Cell Rep
2015
;
13
:
1623
32
.
31.
Seidel
JJ
,
Anderson
CM
,
Blackburn
EH
. 
A novel Tel1/ATM N-terminal motif, TAN, is essential for telomere length maintenance and a DNA damage response
.
Mol Cell Biol
2008
;
28
:
5736
46
.
32.
Palazzo
L
,
Della Monica
R
,
Visconti
R
,
Costanzo
V
,
Grieco
D
. 
ATM controls proper mitotic spindle structure
.
Cell Cycle
2014
;
13
:
1091
100
.
33.
Carney
JP
,
Maser
RS
,
Olivares
H
,
Davis
EM
,
Le Beau
M
,
Yates
JR
 3rd
, et al
The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response
.
Cell
1998
;
93
:
477
86
.
34.
You
Z
,
Chahwan
C
,
Bailis
J
,
Hunter
T
,
Russell
P
. 
ATM activation and its recruitment to damaged DNA require binding to the C terminus of Nbs1
.
Mol Cell Biol
2005
;
25
:
5363
79
.
35.
Sun
Y
,
Xu
Y
,
Roy
K
,
Price
BD
. 
DNA damage-induced acetylation of lysine 3016 of ATM activates ATM kinase activity
.
Mol Cell Biol
2007
;
27
:
8502
9
.
36.
Bakkenist
CJ
,
Kastan
MB
. 
DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
.
Nature
2003
;
421
:
499
506
.
37.
Lau
WC
,
Li
Y
,
Liu
Z
,
Gao
Y
,
Zhang
Q
,
Huen
MS
. 
Structure of the human dimeric ATM kinase
.
Cell Cycle
2016
;
15
:
1117
24
.
38.
Lavin
MF
,
Kozlov
S
. 
ATM activation and DNA damage response
.
Cell Cycle
2007
;
6
:
931
42
.
39.
Mochan
TA
,
Venere
M
,
DiTullio
RA
 Jr
,
Halazonetis
TD
. 
53BP1 and NFBD1/MDC1-Nbs1 function in parallel interacting pathways activating ataxia-telangiectasia mutated (ATM) in response to DNA damage
.
Cancer Res
2003
;
63
:
8586
91
.
40.
Choi
M
,
Kipps
T
,
Kurzrock
R
. 
ATM mutations in cancer: therapeutic implications
.
Mol Cancer Ther
2016
;
15
:
1781
91
.
41.
Stredrick
DL
,
Garcia-Closas
M
,
Pineda
MA
,
Bhatti
P
,
Alexander
BH
,
Doody
MM
, et al
The ATM missense mutation p.Ser49Cys (c.146C>G) and the risk of breast cancer
.
Hum Mutat
2006
;
27
:
538
44
.
42.
Dombernowsky
SL
,
Weischer
M
,
Allin
KH
,
Bojesen
SE
,
Tybjaerg-Hansen
A
,
Nordestgaard
BG
. 
Risk of cancer by ATM missense mutations in the general population
.
J Clin Oncol
2008
;
26
:
3057
62
.
43.
Jones
S
,
Zhang
X
,
Parsons
DW
,
Lin
JC
,
Leary
RJ
,
Angenendt
P
, et al
Core signaling pathways in human pancreatic cancers revealed by global genomic analyses
.
Science
2008
;
321
:
1801
6
.
44.
Waddell
N
,
Pajic
M
,
Patch
AM
,
Chang
DK
,
Kassahn
KS
,
Bailey
P
, et al
Whole genomes redefine the mutational landscape of pancreatic cancer
.
Nature
2015
;
518
:
495
501
.
45.
Zhen
DB
,
Rabe
KG
,
Gallinger
S
,
Syngal
S
,
Schwartz
AG
,
Goggins
MG
, et al
BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study
.
Genet Med
2015
;
17
:
569
77
.
46.
Kastrinos
F
,
Mukherjee
B
,
Tayob
N
,
Wang
F
,
Sparr
J
,
Raymond
VM
, et al
Risk of pancreatic cancer in families with Lynch syndrome
.
JAMA
2009
;
302
:
1790
5
.
47.
Russell
R
,
Perkhofer
L
,
Liebau
S
,
Lin
Q
,
Lechel
A
,
Feld
FM
, et al
Loss of ATM accelerates pancreatic cancer formation and epithelial-mesenchymal transition
.
Nat Commun
2015
;
6
:
7677
.
48.
Heeke
AL
,
Pishvaian
MJ
,
Lynce
F
,
Xiu
J
,
Brody
JR
,
Chen
WJ
, et al
Prevalence of homologous recombination-related gene mutations across multiple cancer types
.
JCO Precis Oncol
2018
;
2018
. doi:
10.1200/PO.17.00286
.
49.
Murphy
SJ
,
Hart
SN
,
Lima
JF
,
Kipp
BR
,
Klebig
M
,
Winters
JL
, et al
Genetic alterations associated with progression from pancreatic intraepithelial neoplasia to invasive pancreatic tumor
.
Gastroenterology
2013
;
145
:
1098
109
.
e1
.
50.
Kim
H
,
Saka
B
,
Knight
S
,
Borges
M
,
Childs
E
,
Klein
A
, et al
Having pancreatic cancer with tumoral loss of ATM and normal TP53 protein expression is associated with a poorer prognosis
.
Clin Cancer Res
2014
;
20
:
1865
72
.
51.
Grant
RC
,
Selander
I
,
Connor
AA
,
Selvarajah
S
,
Borgida
A
,
Briollais
L
, et al
Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer
.
Gastroenterology
2015
;
148
:
556
64
.
52.
Connor
AA
,
Denroche
RE
,
Jang
GH
,
Timms
L
,
Kalimuthu
SN
,
Selander
I
, et al
Association of distinct mutational signatures with correlates of increased immune activity in pancreatic ductal adenocarcinoma
.
JAMA Oncol
2017
;
3
:
774
83
.
53.
Shahda
S
,
Timms
K
,
Ibrahim
A
,
Reid
JE
,
Cramer
HM
,
Radovich
M
, et al
Homologous recombination deficiency (HRD) in patients with pancreatic cance
r (PS) and response to chemotherapy
.
American Society of Clinical Oncology Gastrointestinal Cancer Symposium
; 
2016
Jan 21–23;
San Francisco, CA. Abstract 317
.
54.
Shindo
K
,
Yu
J
,
Suenaga
M
,
Fesharakizadeh
S
,
Cho
C
,
Macgregor-Das
A
, et al
Deleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma
.
J Clin Oncol
2017
;
35
:
3382
90
.
55.
Hu
C
,
Hart
SN
,
Polley
EC
,
Gnanaolivu
R
,
Shimelis
H
,
Lee
KY
, et al
Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer
.
JAMA
2018
;
319
:
2401
9
.
56.
Ohmoto
A
,
Morizane
C
,
Kubo
E
,
Takai
E
,
Hosoi
H
,
Sakamoto
Y
, et al
Germline variants in pancreatic cancer patients with a personal or family history of cancer fulfilling the revised Bethesda guidelines
.
J Gastroenterol
2018
;
53
:
1159
67
.
57.
Chaffee
KG
,
Oberg
AL
,
McWilliams
RR
,
Majithia
N
,
Allen
BA
,
Kidd
J
, et al
Prevalence of germ-line mutations in cancer genes among pancreatic cancer patients with a positive family history
.
Genet Med
2018
;
20
:
119
27
.
58.
Yurgelun
MB
,
Chittenden
AB
,
Morales-Oyarvide
V
,
Rubinson
DA
,
Dunne
RF
,
Kozak
MM
, et al
Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer
.
Genet Med
2019
;
21
:
213
23
.
59.
Weigelt
B
,
Bi
R
,
Kumar
R
,
Blecua
P
,
Mandelker
DL
,
Geyer
FC
, et al
The landscape of somatic genetic alterations in breast cancers from ATM germline mutation carriers
.
J Natl Cancer Inst
2018
;
110
:
1030
4
.
60.
Lowery
MA
,
Wong
W
,
Jordan
EJ
,
Lee
JW
,
Kemel
Y
,
Vijai
J
, et al
Prospective evaluation of germline alterations in patients with exocrine pancreatic neoplasms
.
J Natl Cancer Inst
2018
;
110
:
1067
74
.
61.
Lord
CJ
,
Ashworth
A
. 
PARP inhibitors: synthetic lethality in the clinic
.
Science
2017
;
355
:
1152
8
.
62.
Perkhofer
L
,
Schmitt
A
,
Romero Carrasco
MC
,
Ihle
M
,
Hampp
S
,
Ruess
DA
, et al
ATM deficiency generating genomic instability sensitizes pancreatic ductal adenocarcinoma cells to therapy-induced DNA damage
.
Cancer Res
2017
;
77
:
5576
90
.
63.
Taylor
AM
,
Metcalfe
JA
,
Oxford
JM
,
Harnden
DG
. 
Is chromatid-type damage in ataxia telangiectasia after irradiation at G0 a consequence of defective repair?
Nature
1976
;
260
:
441
3
.
64.
Wang
L
,
Lawrence
T
,
Xu
L
,
Canman
C
,
Ljungman
M
,
Simeone
D
, et al
Radiation-induced phosphorylation of ATDC via ATM/MAPKAP kinase 2 signaling mediates radioresistance of pancreatic cancer cells
.
[abstract]. In:
Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18–21,
, 
2012
;
Lake Tahoe, NV. Philadelphia (PA)
:
AACR
;
Cancer Res 2012;72(12 Suppl):Abstract nr A93
.
65.
Ayars
M
,
Eshleman
J
,
Goggins
M
. 
Susceptibility of ATM-deficient pancreatic cancer cells to radiation
.
Cell Cycle
2017
;
16
:
991
8
.
66.
Pennington
KP
,
Walsh
T
,
Harrell
MI
,
Lee
MK
,
Pennil
CC
,
Rendi
MH
, et al
Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas
.
Clin Cancer Res
2014
;
20
:
764
75
.
67.
Jiang
H
,
Reinhardt
HC
,
Bartkova
J
,
Tommiska
J
,
Blomqvist
C
,
Nevanlinna
H
, et al
The combined status of ATM and p53 link tumor development with therapeutic response
.
Genes Dev
2009
;
23
:
1895
909
.
68.
Fedier
A
,
Schlamminger
M
,
Schwarz
VA
,
Haller
U
,
Howell
SB
,
Fink
D
. 
Loss of atm sensitises p53-deficient cells to topoisomerase poisons and antimetabolites
.
Ann Oncol
2003
;
14
:
938
45
.
69.
Kondo
T
,
Kanai
M
,
Kou
T
,
Sakuma
T
,
Mochizuki
H
,
Kamada
M
, et al
Association between homologous recombination repair gene mutations and response to oxaliplatin in pancreatic cancer
.
Oncotarget
2018
;
9
:
19817
25
.
70.
O'Connor
MJ
. 
Targeting the DNA damage response in cancer
.
Mol Cell
2015
;
60
:
547
60
.
71.
Brown
JS
,
O'Carrigan
B
,
Jackson
SP
,
Yap
TA
. 
Targeting DNA repair in cancer: beyond PARP inhibitors
.
Cancer Discov
2017
;
7
:
20
37
.
72.
Sarkaria
JN
,
Tibbetts
RS
,
Busby
EC
,
Kennedy
AP
,
Hill
DE
,
Abraham
RT
. 
Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin
.
Cancer Res
1998
;
58
:
4375
82
.
73.
Hickson
I
,
Zhao
Y
,
Richardson
CJ
,
Green
SJ
,
Martin
NM
,
Orr
AI
, et al
Identification and characterization of a novel and specific inhibitor of the ataxia-telangiectasia mutated kinase ATM
.
Cancer Res
2004
;
64
:
9152
9
.
74.
Greene
J
,
Nguyen
A
,
Bagby
SM
,
Jones
GN
,
Tai
WM
,
Quackenbush
KS
, et al
The novel ATM inhibitor (AZ31) enhances antitumor activity in patient derived xenografts that are resistant to irinotecan monotherapy
.
Oncotarget
2017
;
8
:
110904
13
.
75.
Golding
SE
,
Rosenberg
E
,
Valerie
N
,
Hussaini
I
,
Frigerio
M
,
Cockcroft
XF
, et al
Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion
.
Mol Cancer Ther
2009
;
8
:
2894
902
.
76.
Saldivar
JC
,
Cortez
D
,
Cimprich
KA
. 
The essential kinase ATR: ensuring faithful duplication of a challenging genome
.
Nat Rev Mol Cell Biol
2017
;
18
:
622
36
.
77.
Olsen
BB
,
Fritz
G
,
Issinger
OG
. 
Characterization of ATM and DNA-PK wild-type and mutant cell lines upon DSB induction in the presence and absence of CK2 inhibitors
.
Int J Oncol
2012
;
40
:
592
8
.
78.
Schoppy
DW
,
Ragland
RL
,
Gilad
O
,
Shastri
N
,
Peters
AA
,
Murga
M
, et al
Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR
.
J Clin Invest
2012
;
122
:
241
52
.
79.
Neubauer
S
,
Arutyunyan
R
,
Stumm
M
,
Dork
T
,
Bendix
R
,
Bremer
M
, et al
Radiosensitivity of ataxia telangiectasia and Nijmegen breakage syndrome homozygotes and heterozygotes as determined by three-color FISH chromosome painting
.
Radiat Res
2002
;
157
:
312
21
.
80.
Moding
EJ
,
Lee
CL
,
Castle
KD
,
Oh
P
,
Mao
L
,
Zha
S
, et al
Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endothelium
.
J Clin Invest
2014
;
124
:
3325
38
.
81.
Schmitt
A
,
Knittel
G
,
Welcker
D
,
Yang
TP
,
George
J
,
Nowak
M
, et al
ATM deficiency is associated with sensitivity to PARP1- and ATR inhibitors in lung adenocarcinoma
.
Cancer Res
2017
;
77
:
3040
56
.
82.
Bang
YJ
,
Im
SA
,
Lee
KW
,
Cho
JY
,
Song
EK
,
Lee
KH
, et al
Randomized, double-blind phase II trial with prospective classification by ATM protein level to evaluate the efficacy and tolerability of olaparib plus paclitaxel in patients with recurrent or metastatic gastric cancer
.
J Clin Oncol
2015
;
33
:
3858
65
.
83.
Bang
YJ
,
Xu
RH
,
Chin
K
,
Lee
KW
,
Park
SH
,
Rha
SY
, et al
Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD): a double-blind, randomised, placebo-controlled, phase 3 trial
.
Lancet Oncol
2017
;
18
:
1637
51
.
84.
Yoo
HY
,
Kumagai
A
,
Shevchenko
A
,
Shevchenko
A
,
Dunphy
WG
. 
Ataxia-telangiectasia mutated (ATM)-dependent activation of ATR occurs through phosphorylation of TopBP1 by ATM
.
J Biol Chem
2007
;
282
:
17501
6
.
85.
Jackson
SP
,
Bartek
J
. 
The DNA-damage response in human biology and disease
.
Nature
2009
;
461
:
1071
8
.
86.
Bolt
J
,
Vo
QN
,
Kim
WJ
,
McWhorter
AJ
,
Thomson
J
,
Hagensee
ME
, et al
The ATM/p53 pathway is commonly targeted for inactivation in squamous cell carcinoma of the head and neck (SCCHN) by multiple molecular mechanisms
.
Oral Oncol
2005
;
41
:
1013
20
.
87.
Reaper
PM
,
Griffiths
MR
,
Long
JM
,
Charrier
JD
,
Maccormick
S
,
Charlton
PA
, et al
Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR
.
Nat Chem Biol
2011
;
7
:
428
30
.
88.
Min
A
,
Im
SA
,
Jang
H
,
Kim
S
,
Lee
M
,
Kim
DK
, et al
AZD6738, a novel oral inhibitor of ATR, induces synthetic lethality with ATM deficiency in gastric cancer cells
.
Mol Cancer Ther
2017
;
16
:
566
77
.
89.
Shi
Q
,
Shen
LY
,
Dong
B
,
Fu
H
,
Kang
XZ
,
Yang
YB
, et al
The identification of the ATR inhibitor VE-822 as a therapeutic strategy for enhancing cisplatin chemosensitivity in esophageal squamous cell carcinoma
.
Cancer Lett
2018
;
432
:
56
68
.
90.
Vendetti
FP
,
Lau
A
,
Schamus
S
,
Conrads
TP
,
O'Connor
MJ
,
Bakkenist
CJ
. 
The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo
.
Oncotarget
2015
;
6
:
44289
305
.
91.
Engelke
CG
,
Parsels
LA
,
Qian
Y
,
Zhang
Q
,
Karnak
D
,
Robertson
JR
, et al
Sensitization of pancreatic cancer to chemoradiation by the Chk1 inhibitor MK8776
.
Clin Cancer Res
2013
;
19
:
4412
21
.
92.
Liang
M
,
Zhao
T
,
Ma
L
,
Guo
Y
. 
CHK1 inhibition sensitizes pancreatic cancer cells to gemcitabine via promoting CDK-dependent DNA damage and ribonucleotide reductase downregulation
.
Oncol Rep
2018
;
39
:
1322
30
.
93.
Al-Ejeh
F
,
Pajic
M
,
Shi
W
,
Kalimutho
M
,
Miranda
M
,
Nagrial
AM
, et al
Gemcitabine and CHK1 inhibition potentiate EGFR-directed radioimmunotherapy against pancreatic ductal adenocarcinoma
.
Clin Cancer Res
2014
;
20
:
3187
97
.
94.
Kawamura
D
,
Takemoto
Y
,
Nishimoto
A
,
Ueno
K
,
Hosoyama
T
,
Shirasawa
B
, et al
Enhancement of cytotoxic effects of gemcitabine by Dclk1 inhibition through suppression of Chk1 phosphorylation in human pancreatic cancer cells
.
Oncol Rep
2017
;
38
:
3238
44
.
95.
Duong
HQ
,
Hong
YB
,
Kim
JS
,
Lee
HS
,
Yi
YW
,
Kim
YJ
, et al
Inhibition of checkpoint kinase 2 (CHK2) enhances sensitivity of pancreatic adenocarcinoma cells to gemcitabine
.
J Cell Mol Med
2013
;
17
:
1261
70
.
96.
Hallahan
D
. 
ATM inhibition sensitizes tumors to high-dose irradiation
.
Cancer Res
2019
;
79
:
704
5
.
97.
Sen
T
,
Rodriguez
BL
,
Chen
L
,
Della Corte
C
,
Morikawa
N
,
Fujimoto
J
, et al
Targeting DNA damage response promotes anti-tumor immunity through STING-mediated T-cell activation in small cell lung cancer
.
Cancer Discov
2019
;
9
:
646
61
.
98.
van Os
NJH
,
Chessa
L
,
Weemaes
CMR
,
van Deuren
M
,
Fievet
A
,
van Gaalen
J
, et al
Genotype-phenotype correlations in ataxia telangiectasia patients with ATM c.3576G>A and c.8147T>C mutations
.
J Med Genet
2019
;
56
:
308
16
.
99.
Drosos
Y
,
Escobar
D
,
Chiang
MY
,
Roys
K
,
Valentine
V
,
Valentine
MB
, et al
ATM-deficiency increases genomic instability and metastatic potential in a mouse model of pancreatic cancer
.
Sci Rep
2017
;
7
:
11144
.