Drugs targeting DNA damage repair (DDR) pathways are exciting new agents in cancer therapy. Many of these drugs exhibit synthetic lethality with defects in DNA repair in cancer cells. For example, ovarian cancers with impaired homologous recombination DNA repair show increased sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Understanding the activity of different DNA repair pathways in individual tumors, and the correlations between DNA repair function and drug response, will be critical to patient selection for DNA repair targeted agents. Genomic and functional assays of DNA repair pathway activity are being investigated as potential biomarkers of response to targeted therapies. Furthermore, alterations in DNA repair function generate resistance to DNA repair targeted agents, and DNA repair states may predict intrinsic or acquired drug resistance. In this review, we provide an overview of DNA repair targeted agents currently in clinical trials and the emerging biomarkers of response and resistance to these agents: genetic and genomic analysis of DDR pathways, genomic signatures of mutational processes, expression of DNA repair proteins, and functional assays for DNA repair capacity. We review biomarkers that may predict response to selected DNA repair targeted agents, including PARP inhibitors, inhibitors of the DNA damage sensors ATM and ATR, and inhibitors of nonhomologous end joining. Finally, we introduce emerging categories of drugs targeting DDR and new strategies for integrating DNA repair targeted therapies into clinical practice, including combination regimens. Generating and validating robust biomarkers will optimize the efficacy of DNA repair targeted therapies and maximize their impact on cancer treatment. Clin Cancer Res; 22(23); 5651–60. ©2016 AACR.

Normal and cancer cells rely on multiple DNA damage response (DDR) pathways specialized to repair specific forms of DNA damage (Table 1; refs. 1–4). Key pathways include base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination repair (HRR), nonhomologous end-joining (NHEJ), and interstrand crosslink repair (ICL). If canonical repair pathways are deficient, or repair is unsuccessful, error-prone alternative pathways may be employed (e.g., alt-NHEJ, single-strand annealing, or translesion synthesis; refs. 1–4).

Table 1.

DDR pathways and associated signaling pathways

MechanismType of damageFunctionKey genesInhibitors of pathway proteins
DNA damage recognition, signaling, and checkpoints 
DNA double-strand break recognition – Double-strand breaks (DSB) – Recognition of DNA damage and recruitment of repair machinery MRN complex: MRE11, RAD50, NBN (NBS1) PARP inhibitors 
   RBBP8 (CTIP) MRE11 inhibitors (e.g., mirin) 
   PARP1  
DNA repair checkpoints Various – Coordination of cell cycle with DNA repair ATM ATM inhibitors 
  – Induction of cell death for irreparable lesions ATR ATR inhibitors 
   CHEK1 (Chk1) Chk1/2 inhibitors 
   CHEK2 (Chk2) Wee1 inhibitors 
   TP53 (p53)  
   H2AFX (Histone H2A.X)  
Cell-cycle checkpoints Various – Regulate cell cycle to allow time for DNA repair activities and coordinate repair with progression through cell cycle Genes encoding cyclin/CDK proteins CDK inhibitors 
Replication stress response – Slowing/stalling of replicative DNA polymerase progression due to a variety of cellular stresses, resulting in stalled replication forks. – Stabilization of stalled replication forks and DNA repair to enable replication restart. If this fails, DNA damage (e.g., DSBs) can result. RPA1, RPA2 ATR inhibitors 
   ATR Chk1 inhibitors 
   ATRIP  
   CHEK1 (Chk1)  
   TOPBP1  
DNA repair pathways 
Direct repair – Base modifications, including O6-methylguanine, 1-methyladenine, 3-methylcytosine, and N-methylated adenosine and cytosine – Direct repair of modified bases by enzymatic processes: demethylation MGMT ALKBH1 MGMT inhibitors 
 – Examples: alkylating agents    
Base excision repair (BER)– Short patch repair – Long patch repair– Single-strand break repair – Damaged and modified bases– Single-strand breaks– Examples: radiotherapy, alkylating agents – Excision of damaged base to generate a basic site, followed by nicking, resynthesis, and single-strand break repair (SSBR) OGG1 APE-1 inhibitors 
   NEIL1, NEIL2, NEIL3 PARP inhibitors 
   APEX1 PNKP inhibitors 
   PARP1, PARP2 POLB inhibitors 
   XRCC1  
   POLB  
   LIG1  
   LIG3  
   FEN1  
   PNKP  
   MUTYH  
Nucleotide excision repair (NER) – Transcription- coupled NER – Global NER – Bulky DNA adducts – Damage recognition and unwinding of local DNA, nuclease excision, resynthesis, and SSBR RAD23B  
 – Inter- and intrastrand crosslinks  DDB1  
 – Examples: platinum agents, ultraviolet (UV) light  RPA1, RPA2  
   ERCC1, ERCC2 (XPD), ERCC3, ERCC5, ERCC6, ERCC8  
   GTF2H1, GTF2H2, GTF2H4, GTF2H5, GTF2F2  
   CDK7  
   MMS19  
   MNAT1  
   XPA, XPC  
   CCNH  
   PCNA  
   RFC1  
Mismatch repair (MMR) – Base mismatches (single nucleotide mutations and small insertions/deletions) – Examples: alkylating agents, replication errors – Recognition and removal of mismatched base followed by resynthesis of correct base and SSBR MLH1  
   MLH3  
   MSH2  
   MSH6  
   PMS2  
Homologous recombination repair (HRR) – Double-strand breaks – Examples: radiation, topoisomerase inhibitors, cisplatin – Unwinding and resection at DSB to generate single-strand end, strand invasion, homologous recombination with sister chromatid, resynthesis, and resolution. Results in exact repair using sequences from sister chromatid. BRCA1 BRCA2 RAD51, RAD52 TP53BP1 RAD51/2 inhibitors BLM inhibitors 
   RBBP8 (CTIP)  
   EXO1  
   RPA1, RPA2  
   BLM  
   PALB2  
   MRN complex: MRE11, RAD50, NBN (NBS1)  
Interstrand crosslink repair (ICL) – Interstrand crosslinks – Examples: platinum agents, nitrogen mustards, mitomycin C – Crosslinks are excised and then repaired by HRR (or other mechanisms) BRCA2  
   FANCA  
   FANCB  
   FANCC  
   FANCD2  
   FANCE  
   FANCG  
   FANCF  
   FANCI  
   FANCL  
   BRIP1  
   FANCM  
   FAAP20  
   FAAP100  
Nonhomologous end joining (NHEJ) – Classical NHEJ – Alternative NHEJ or microhomology-mediated end joining – Double-strand breaks – Examples: radiation, topoisomerase inhibitors, cisplatin – Processing and re-ligation of double-strand break ends. Error prone due to processing steps and because the homologous template is not used for repair. PRKDC (DNA-PKcs) DNA-PK inhibitors 
   XRCC5 (Ku80), XRCC6 (Ku70)  
   LIG4  
   XRCC4  
   POLQ  
   NHEJ1  
   DCLRE1C (Artemis)  
   PARP1, PARP2  
   XRCC1  
Single-strand annealing – Double-strand breaks – Homology-mediated repair of repetitive regions RPA1, RPA2  
   RAD52  
Translesion synthesis (damage bypass rather than repair) – DNA adducts – Error-prone polymerases synthesize DNA past regions of damage, especially bulky DNA adducts POLH  
 – Examples: platinum agents, UV light    
MechanismType of damageFunctionKey genesInhibitors of pathway proteins
DNA damage recognition, signaling, and checkpoints 
DNA double-strand break recognition – Double-strand breaks (DSB) – Recognition of DNA damage and recruitment of repair machinery MRN complex: MRE11, RAD50, NBN (NBS1) PARP inhibitors 
   RBBP8 (CTIP) MRE11 inhibitors (e.g., mirin) 
   PARP1  
DNA repair checkpoints Various – Coordination of cell cycle with DNA repair ATM ATM inhibitors 
  – Induction of cell death for irreparable lesions ATR ATR inhibitors 
   CHEK1 (Chk1) Chk1/2 inhibitors 
   CHEK2 (Chk2) Wee1 inhibitors 
   TP53 (p53)  
   H2AFX (Histone H2A.X)  
Cell-cycle checkpoints Various – Regulate cell cycle to allow time for DNA repair activities and coordinate repair with progression through cell cycle Genes encoding cyclin/CDK proteins CDK inhibitors 
Replication stress response – Slowing/stalling of replicative DNA polymerase progression due to a variety of cellular stresses, resulting in stalled replication forks. – Stabilization of stalled replication forks and DNA repair to enable replication restart. If this fails, DNA damage (e.g., DSBs) can result. RPA1, RPA2 ATR inhibitors 
   ATR Chk1 inhibitors 
   ATRIP  
   CHEK1 (Chk1)  
   TOPBP1  
DNA repair pathways 
Direct repair – Base modifications, including O6-methylguanine, 1-methyladenine, 3-methylcytosine, and N-methylated adenosine and cytosine – Direct repair of modified bases by enzymatic processes: demethylation MGMT ALKBH1 MGMT inhibitors 
 – Examples: alkylating agents    
Base excision repair (BER)– Short patch repair – Long patch repair– Single-strand break repair – Damaged and modified bases– Single-strand breaks– Examples: radiotherapy, alkylating agents – Excision of damaged base to generate a basic site, followed by nicking, resynthesis, and single-strand break repair (SSBR) OGG1 APE-1 inhibitors 
   NEIL1, NEIL2, NEIL3 PARP inhibitors 
   APEX1 PNKP inhibitors 
   PARP1, PARP2 POLB inhibitors 
   XRCC1  
   POLB  
   LIG1  
   LIG3  
   FEN1  
   PNKP  
   MUTYH  
Nucleotide excision repair (NER) – Transcription- coupled NER – Global NER – Bulky DNA adducts – Damage recognition and unwinding of local DNA, nuclease excision, resynthesis, and SSBR RAD23B  
 – Inter- and intrastrand crosslinks  DDB1  
 – Examples: platinum agents, ultraviolet (UV) light  RPA1, RPA2  
   ERCC1, ERCC2 (XPD), ERCC3, ERCC5, ERCC6, ERCC8  
   GTF2H1, GTF2H2, GTF2H4, GTF2H5, GTF2F2  
   CDK7  
   MMS19  
   MNAT1  
   XPA, XPC  
   CCNH  
   PCNA  
   RFC1  
Mismatch repair (MMR) – Base mismatches (single nucleotide mutations and small insertions/deletions) – Examples: alkylating agents, replication errors – Recognition and removal of mismatched base followed by resynthesis of correct base and SSBR MLH1  
   MLH3  
   MSH2  
   MSH6  
   PMS2  
Homologous recombination repair (HRR) – Double-strand breaks – Examples: radiation, topoisomerase inhibitors, cisplatin – Unwinding and resection at DSB to generate single-strand end, strand invasion, homologous recombination with sister chromatid, resynthesis, and resolution. Results in exact repair using sequences from sister chromatid. BRCA1 BRCA2 RAD51, RAD52 TP53BP1 RAD51/2 inhibitors BLM inhibitors 
   RBBP8 (CTIP)  
   EXO1  
   RPA1, RPA2  
   BLM  
   PALB2  
   MRN complex: MRE11, RAD50, NBN (NBS1)  
Interstrand crosslink repair (ICL) – Interstrand crosslinks – Examples: platinum agents, nitrogen mustards, mitomycin C – Crosslinks are excised and then repaired by HRR (or other mechanisms) BRCA2  
   FANCA  
   FANCB  
   FANCC  
   FANCD2  
   FANCE  
   FANCG  
   FANCF  
   FANCI  
   FANCL  
   BRIP1  
   FANCM  
   FAAP20  
   FAAP100  
Nonhomologous end joining (NHEJ) – Classical NHEJ – Alternative NHEJ or microhomology-mediated end joining – Double-strand breaks – Examples: radiation, topoisomerase inhibitors, cisplatin – Processing and re-ligation of double-strand break ends. Error prone due to processing steps and because the homologous template is not used for repair. PRKDC (DNA-PKcs) DNA-PK inhibitors 
   XRCC5 (Ku80), XRCC6 (Ku70)  
   LIG4  
   XRCC4  
   POLQ  
   NHEJ1  
   DCLRE1C (Artemis)  
   PARP1, PARP2  
   XRCC1  
Single-strand annealing – Double-strand breaks – Homology-mediated repair of repetitive regions RPA1, RPA2  
   RAD52  
Translesion synthesis (damage bypass rather than repair) – DNA adducts – Error-prone polymerases synthesize DNA past regions of damage, especially bulky DNA adducts POLH  
 – Examples: platinum agents, UV light    

NOTE: DDR pathways and therapeutic targets. Summary of DNA damage repair pathways, their functions, and key proteins, as well as classes of DNA repair targeted agents that inhibit different pathways.

Abbreviation: DNA-PKcs, DNA-dependent protein kinase catalyic subunit.

DNA repair targeted therapies exploit DNA repair defects in cancer cells to generate synthetic lethality (cell death resulting from simultaneous loss or inhibition of two critical functions; for example, cancer cells defective in one DNA repair pathway rely on alternate repair pathways; inhibition of a second repair pathway then results in cell death, an effect which selectively targets repair-deficient cancer cells; refs. 5, 6). DNA repair defects vary by cancer type. For example, approximately 50% of ovarian carcinomas (OC) exhibit dysfunctional HRR (7–10), colon and endometrial cancers are enriched in MMR defects (11), bladder cancers have frequent NER mutations (12), and testicular germ cell tumors may be functionally deficient in NER and other DDR pathways (13, 14). Many biomarkers for response to DNA repair targeted therapies reflect specific alterations in DDR pathways or genomic signatures resulting from aberrant repair.

Cytotoxic chemotherapies induce particular forms of DNA damage that trigger specific repair pathways. Therefore, cancers with DNA repair deficiencies show increased sensitivity to certain chemotherapeutics. For instance, OC patients with germline BRCA1 or BRCA2 (BRCA1/2) mutations (HRR deficiency) and bladder cancer patients with somatic ERCC2 mutations (NER pathway) are more sensitive to platinum agents (15), likely due to decreased capacity to repair platinum-induced DNA damage. HRR and BER deficiencies sensitize cancer cells to topoisomerase-I inhibitors (e.g., topotecan), whereas HRR and NHEJ deficiencies sensitize to topoisomerase-II inhibitors (e.g., doxorubicin and etoposide; ref. 16).

HRR deficiency confers sensitivity to inhibitors of the PARP enzyme, which is vital to several DNA repair pathways, including BER and NHEJ. Developing biomarkers of DDR function and correlating DNA repair capacity with sensitivity to targeted agents is critical to optimizing efficacy of targeted DNA repair drugs. In this review, we describe candidate biomarkers of response (and resistance) to DNA repair targeted therapies. Genomic sequencing studies have demonstrated frequent DDR alterations in diverse cancers, suggesting that DNA repair targeted agents may be broadly active in cancer therapy and highlighting the need for accurate biomarkers of response (17, 18).

PARP inhibitors (PARPi) are selectively lethal to HRR-deficient cells (19, 20). Synthetic lethality may be mediated by PARPi impairment of BER, although at least six potential mechanisms of action have been suggested, including alterations in NHEJ, alternative end joining, and DNA repair protein recruitment; PARP trapping at the replication fork is particularly significant, generating increased double-strand breaks (DSB) and dependence upon HRR (10, 21). Different PARPi may vary in their specificity for PARP enzymes and PARP trapping activity. Identifying the clinically relevant mechanisms of PARPi activity and resistance will be important to selecting optimal biomarkers.

Olaparib was the first FDA-approved PARPi after clinical trials showed benefit in OC and other cancers, primarily in patients with germline BRCA1/2 mutations (21–24). Olaparib is approved in the United States for patients with recurrent OC who have a germline BRCA1/2 mutation and in whom at least 3 lines of therapy have failed. Clinical trials of various PARPi in diverse clinical contexts and in combination with several agents are summarized in Supplementary Table S1. When PARPi are used as a single agent, resistance typically develops in months, though occasional sustained responses are observed (24).

The success of PARPi in patients with germline BRCA1/2 mutations and clinical trials showing better response rates in cancers with germline and somatic BRCA1/2 mutations than in those without have confirmed that damaging BRCA1/2 mutations (suggesting HRR deficiency) are an important biomarker for PARPi sensitivity (24). Restoration of HRR function by somatic reversion of germline BRCA1/2 mutations confers platinum and PARPi resistance in OC (25, 26).

Because sensitivity to platinum and PARPi are both associated with HRR defects, platinum sensitivity has been used as a surrogate for HRR deficiency in OC. However, some patients with platinum sensitivity do not respond to PARPi, and trials of PARPi in unselected patients have produced responses in a subset of patients with platinum resistance (27). Hence, platinum and PARPi responsiveness are not always concordant. Variability in DNA repair function may underlie this complexity: NER gene mutations are associated with platinum sensitivity in OC patients and cell lines but exhibit resistance to PARPi in vitro (28), and PARPi resistance mechanisms, such as loss of TP53BP1 or REV7, may be associated with platinum sensitivity (29, 30).

Clinically feasible, accurate biomarkers for response and resistance to PARPi are needed. Numerous assays for HRR deficiency are available, each with advantages and disadvantages (Table 2) as well as varying capability to predict PARPi response that must be tested in prospective clinical trials.

Table 2.

Assays for HRR function

AssayExamplesAdvantagesDisadvantages
Targeted sequencing – Specific gene panels – Whole-exome sequencing – Can assess many DNA repair genes simultaneously – Must know a priori which genes will have clinical impact 
  – Can identify both somatic and germline alterations – Functional impact of many variants uncertain 
Whole-genome sequencing – Mutational signatures of DNA repair deficiency – Not reliant on identifying mutations in specific genes – Expensive – Requires advanced bioinformatics 
Copy number analyses – Loss of heterozygosity – Telomeric allelic imbalance – Large-scale transitions – Not reliant on identifying mutations in specific genes – Historical, rather than dynamic, biomarker 
  – Some commercial assays are in clinical development  
Gene-expression profiling – Expression arrays – Global readout from many upstream inputs and genetic alterations – Poorly reproducible between studies – Can be confounded by tumor/normal mixtures 
 – RNA-Seq – Tractable for use in the clinic  
 – NanoString – Potential for real-time readout – Requires tissue biopsy for dynamic readout 
 – Quantitative RT-PCR   
Protein expression assays – Immunohistochemistry (IHC) – IHC is applicable to small clinical samples – Difficult to identify reliable markers of DNA repair activity 
 – Mass spectrometry–based methods – Can reflect functional impact of alterations in DNA and RNA – Depending on the assay, can be poorly reproducible 
 – Protein chips – Potentially dynamic readout – Require tissue biopsy for real-time assessment 
Functional assays – RAD51 foci formation – Directly reflect DNA repair capacity – Difficult to apply in clinical practice—most require fresh tissue and exposure to DNA damage 
 – γ-H2AX – Integrate functional effects of multiple levels of cellular alterations (DNA, RNA, protein)  
 – PARylation   
 – Phospho-NBS1 (NBN)   
 – DNA fiber assay   
 – RPA foci   
AssayExamplesAdvantagesDisadvantages
Targeted sequencing – Specific gene panels – Whole-exome sequencing – Can assess many DNA repair genes simultaneously – Must know a priori which genes will have clinical impact 
  – Can identify both somatic and germline alterations – Functional impact of many variants uncertain 
Whole-genome sequencing – Mutational signatures of DNA repair deficiency – Not reliant on identifying mutations in specific genes – Expensive – Requires advanced bioinformatics 
Copy number analyses – Loss of heterozygosity – Telomeric allelic imbalance – Large-scale transitions – Not reliant on identifying mutations in specific genes – Historical, rather than dynamic, biomarker 
  – Some commercial assays are in clinical development  
Gene-expression profiling – Expression arrays – Global readout from many upstream inputs and genetic alterations – Poorly reproducible between studies – Can be confounded by tumor/normal mixtures 
 – RNA-Seq – Tractable for use in the clinic  
 – NanoString – Potential for real-time readout – Requires tissue biopsy for dynamic readout 
 – Quantitative RT-PCR   
Protein expression assays – Immunohistochemistry (IHC) – IHC is applicable to small clinical samples – Difficult to identify reliable markers of DNA repair activity 
 – Mass spectrometry–based methods – Can reflect functional impact of alterations in DNA and RNA – Depending on the assay, can be poorly reproducible 
 – Protein chips – Potentially dynamic readout – Require tissue biopsy for real-time assessment 
Functional assays – RAD51 foci formation – Directly reflect DNA repair capacity – Difficult to apply in clinical practice—most require fresh tissue and exposure to DNA damage 
 – γ-H2AX – Integrate functional effects of multiple levels of cellular alterations (DNA, RNA, protein)  
 – PARylation   
 – Phospho-NBS1 (NBN)   
 – DNA fiber assay   
 – RPA foci   

NOTE: Assays for HRR. Approaches for identifying deficient HRR in cancer, which may affect response to DNA repair targeted therapies.

Abbreviation: RT-PCR, reverse transcriptase PCR.

Targeted sequencing

Targeted multiplex sequencing can identify germline and somatic mutations in DNA repair genes that result in increased or decreased HRR. Although BRCA1/2 mutations are the most prevalent biomarkers in PARPi trials, PARPi responses observed in some BRCA1/2 wild-type patients (27) suggest that alterations in other HRR genes may also confer sensitivity. BROCA is a targeted next-generation sequencing assay that was used to identify damaging mutations in at least one of 13 HRR genes (BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D) in one third of advanced OC; HRR mutations strongly correlated with platinum sensitivity and overall survival (8). Whole-exome sequencing (WES) provides targeted sequencing of most exons, including DNA repair genes, but is not commonly applied in clinical practice. A PARPi clinical trial in metastatic prostate cancer used WES, with an 88% response rate in the one third of patients with HRR gene mutations (31). Variants of uncertain significance (VUS), sequence alterations whose functional significance is unknown, present a particular challenge in clinical practice. Many resources are available to help infer the consequences of VUS [e.g., variant classification databases such as ClinVar, population databases that provide variant frequencies such as the Exome Aggregation Consortium (ExAC) and the Exome Sequencing Project (ESP), and online tools for prediction of variant pathogenicity (PolyPhen-2, SIFT, MutationTaster)]. Nevertheless, the functional and clinical relevance of many VUS remains uncertain, and predictive functional assays for DNA repair genes are needed to improve variant interpretation.

“Genomic scars” (mutational signatures and alterations in genome structure)

Genomic scars represent accumulated patterns of DNA damage and repair identified by genomic profiling (32–34). For example, because cells deficient in HRR rely on more error-prone DNA repair pathways such as NHEJ, large genomic deletions and loss of heterozygosity (LOH) are typical of an HRR phenotype.

Mutational signatures describe genome-wide patterns of nucleotide alterations reflecting historical exposures to DNA damage and repair. Specific mutational signatures are associated with defects in various DDR pathways, including BRCA1/2 (tandem duplications, microhomology mediated deletions) NER (UV light signature), mismatch repair (MMR; microsatellite instability), and POLE (ultramutation signature; ref. 35). Microsatellite instability is a useful clinical test to identify MMR deficiency, which can suggest an underlying inherited disorder (Lynch syndrome). Other mutational signatures may have increasing diagnostic or clinical utility as whole-exome and genome sequencing become more prevalent, such as using mutational signatures suggestive of BRCA1/2 mutations to identify PARPi sensitivity.

Large-scale disarray in chromosome structure is common in HRR-deficient cancers and may be quantitated by several assays including: (i) LOH, patterns of loss of one allele at many sites across the genome, via deletion or copy number neutral LOH; (ii) telomeric allelic imbalance (TAI), allelic imbalance near telomeres; and (iii) large-scale state transitions (LST), chromosomal breaks between adjacent regions of ≥ 10 Mb. LOH quantification correlates with platinum response in OC (36). TAI scores correlate with platinum response in breast cancer and OC and are associated with BRCA1/2 mutations (37). LST is associated with BRCA1/2 alterations in basal-like breast cancer (38). The three scores (LOH, TAI, LST) show a strong correlation with one another (39).

Several HRR deficiency biomarkers using patterns of LOH are being tested as potential companion diagnostics in PARPi clinical trials. An LOH assessment using a sequencing assay from Foundation Medicine was tested as a prospective biomarker in a phase II PARPi clinical trial. In a trial of rucaparib in recurrent OC, response rates were 80%, 29%, and 10%, respectively, in patients with (i) germline and somatic BRCA1/2 mutations, (ii) high LOH but no BRCA1/2 mutation, and (iii) low LOH and no BRCA mutation (40). This suggests that LOH can be used as a surrogate for HRR and predict PARPi response, a hypothesis being tested in multiple prospective trials (e.g., NCT02655016; Supplementary Table S1). Myriad Genetics also developed an HRR deficiency assay based on a combination of LOH, TAI, and LST, which predicts response to neoadjuvant platinum in triple-negative breast cancer (41), and is testing this assay prospectively in multiple PARPi trials. A randomized phase III trial of the PARPi niraparib as maintenance therapy following complete or partial response to platinum in women with recurrent ovarian cancers demonstrated benefit across all subgroups, including those with cancers that tested negative for HRD by the Myriad Genetics HRD assay, though the relative improvement in progression-free survival was greater in patients with HRD (42). Presumably, the genomic scars identified by these assays remain detectable even if functional HRR is re-established, for example, by reversion mutations or epigenetic changes. If true, then LOH profiling might be more predictive of PARPi responsiveness early in the disease course, before various resistance mechanisms have accumulated.

Gene and protein expression

Gene-expression signatures of DDR genes have been described that correlate with outcome and platinum response in ovarian, breast, and lung cancers (43–45). However, a meta-analysis of expression signatures in OC showed that this approach suffers from poor reproducibility (46). Alternatively, HRR protein levels or methylation, for example, by immunohistochemistry, may be useful in revealing dynamic HRR alterations. BRCA1 promoter hypermethylation, which downregulates BRCA1, might contribute to HRR deficiency, and response rates of 52% were recently reported for BRCA1 methylated ovarian cancers treated with the PARPi rucaparib (40). Reversal of BRCA1 hypermethylation was observed in acquired platinum resistance in OC, suggesting that neoplastic cells may re-express silenced BRCA1 as a resistance mechanism (9). BRCA1 expression is further modulated by microRNAs, altering PARPi sensitivity (47). Many studies of HRR protein expression have been limited by small numbers or technical issues, with poor reproducibility or results inconsistent with current models of HRR signaling. Therefore, both gene and protein expression as a biomarker for PARPi or other DNA therapies requires further research and clinical validation (48).

Functional assays

Functional assays can quantitate DNA repair capacity and may provide the most dynamic, real-time readout of DNA repair but are clinically hampered by technical challenges such as the need for fresh tissue and a DNA-damaging stimulus (49). The RAD51 focus formation assay reflects activation of HRR machinery and has been applied to clinical samples. Fewer irradiation-induced RAD51 foci in ex vivo breast cancers and in OC ascites correlated with HRR defects (50, 51) and better response to neoadjuvant chemotherapy (52). Gamma-H2AX foci are increased in the presence of DNA DSBs; foci of 53BP1 also mark DSBs and have been correlated with impaired DSB repair (49, 53). Phospho-NBS1 (p-NBS1) (NBN) marks activation of the MRE11–RAD50–NBN (MRN) complex, which mediates early processing of DSBs (54); nuclear p-NBS1 staining was shown to be feasible in biopsies in a clinical trial of the PARPi veliparib (55). Intratumoral levels and activity of the PARP enzyme are a good pharmacodynamic marker of PARPi activity but do not clearly correlate with clinical responses in patients (55). Similarly, PARP enzyme activity in peripheral blood lymphocytes is a good pharmacodynamic but not predictive biomarker in PARPi clinical trials (56, 57). In vitro cell line studies have shown that HRR deficiency results in hyperactivation of PARP and increased levels of PAR polymers, suggesting that hyperactivated PARP or lower PAR levels may be a marker of PARPi sensitivity or resistance, respectively (58, 59). Clinically, wide variations in PARP activity have been observed among patients, which may limit its utility as a predictive biomarker (60). Changes in PARylation levels have also been used as pharmacokinetic markers of effective PARPi activity (49). Assays for replication stress include the DNA fiber assay (61) and replication protein A (RPA) foci. Certain forms of DNA damage (e.g., bulky adducts) result in stalling of replication forks. Emerging evidence suggests that replication fork stabilization might be a mechanism of resistance to platinum and PARPi independent of HR dysfunction; for instance, Fanconi Anemia group D2 protein (FANCD2) and Pax-interacting protein 1 (PAXIP1, PTIP) can stabilize stalled replication forks, enabling bypass of the blockage and cell survival (62).

These assays represent a wide range of approaches for predicting PARPi response. Selection of optimal, clinically feasible assays awaits validation from clinical trials (Supplementary Table S1).

ATM and ATR kinases are critical components of the early response to DNA damage and activation of cell-cycle checkpoints (reviewed in refs. 63–66). ATM and ATR collaborate with the checkpoint proteins Chk2 and Chk1, respectively, to arrest the cell cycle and allow time for DNA repair. Studies suggest that inhibiting ATM and/or ATR might increase sensitivity to DNA damage. This sensitization may be particularly profound in cells with deficient DNA repair or increased replication stress.

ATM, ATR, and dual ATM/ATR inhibitors have been developed, with several in clinical trials (Table 3, Supplementary Table S1). VX-970 (formerly VE-822) is a potent, selective ATR inhibitor that sensitizes cancer cells with defective DNA repair to chemotherapy (67). Clinical trials are underway combining VX-970 with chemotherapy in advanced malignancies. AZD6738 is another selective ATR inhibitor that is being tested in combination with several agents in phase I trials. AZD0156 is a selective ATM inhibitor that is being studied in combination with olaparib in a phase I trial in advanced cancer; several other ATM inhibitors are undergoing preclinical investigation. Combined ATM/ATR inhibitors are generally less specific, and are not active in clinical trials (reviewed in ref. 66).

Table 3.

DNA repair related therapies in preclinical and clinical development

ClassTarget protein role in DDRClasses of agents and examples of drugs in clinical trialsClinical development phase and contextPotential biomarkers
PARP inhibitors PARP detects single-strand DNA breaks and synthesizes a poly (ADP-ribose) chain (PAR) to recruit repair proteins PARP inhibitors:
  • – Olaparib

  • – Rucaparib

  • – Niraparib

  • – Veliparib

  • – Talazoparib

 
  • Olaparib: FDA-approved in recurrent ovarian cancer with germline BRCA1/2 mutations

  • Others in phase I–III trials in advanced solid malignancies, alone or in combination with chemotherapy, antiangiogenic agents, other targeted agents, and immunotherapy (Supplementary Table S1)

 
Assays for HRR deficiency (Table 2):
  • – Exome sequencing of HRR genes

  • – Mutational signatures

  • – Copy number analyses

  • – Gene and protein expression

  • – Functional assays

 
ATM/ATR inhibitors ATM/ATR: kinases that collaborate with Chk1/2 to arrest cell cycle, allowing time for DNA repair ATR inhibitors:
  • – VX-970

  • – AZD6738

 
VX-970, AZD6738: phase I/II trials combined with chemotherapy or radiation in advanced solid tumors 
  • ATR alterations

  • Alternative lengthening of telomeres

  • ATRX loss

  • DDR deficiency

  • Replication stress

 
  ATM inhibitor:
  • – AZD0156

 
Phase I trial ± PARPi in advanced malignancies 
  • ATM alterations

  • DDR deficiency

  • Replication stress

 
  ATM/ATR inhibitors Preclinical  
NHEJ inhibitors DNA-PK: enzyme complex initiating repair of DSBs by NHEJ (DNA-PKcs = catalytic subunit) DNA-PKcs inhibitors:
  • – CC-122

  • – ZSTK474

  • – CC-115

  • – MSC2490484A

  • – NU7026

  • – NU7441

 
  • MSC2490484A combined with radiation in an ongoing phase I trial

  • CC-115 and CC-122 in phase I trials in advanced malignancies

 
Under development 
 DNA ligase IV: major DNA ligase enzyme in NHEJ DNA ligase IV inhibitors Preclinical Under development 
BER inhibitors AP endonuclease 1 (APE-1) helps remove damaged bases in BER APE-1 inhibitors:
  • – Methoxyamine (TRC102)

  • – Inhibitors of AP endonuclease activity (e.g., lucanthone)

 
Phase I and II combinations with pemetrexed/cisplatin or temozolomide in advanced solid tumors HRR defects may increase sensitivity 
 Bifunctional polynucleotide phosphatase/kinase (PNKP) adds or removes phosphates to DNA ends; also involved in NHEJ PNKP inhibitors Preclinical Under development 
 DNA polymerase beta (POLβ) synthesizes DNA in BER POLβ inhibitors Preclinical Under development 
MRN complex inhibitors (HRR) MRN complex (MRE11A–RAD50– NBN) recognizes DSBs and initiates repair via protein recruitment; MRE11A mediates end resection MRE11 inhibitors (e.g., mirin) Preclinical Under development 
HRR inhibitors RAD51: recombinase promoting homologous recombination RAD51 inhibitors Preclinical Under development 
 DNA helicases unwind DNA in several repair processes Inhibitors of helicases (e.g., BLM, WRN, RECQL1) Preclinical Under development 
Chk1/2 inhibitors Chk1 and Chk2: cell-cycle checkpoint kinases. Chk1 promotes cell-cycle arrest at the G2–M checkpoint and DNA repair. Chk2 promotes the G1 checkpoint and DNA repair. Chk1 inhibitors:
  • – MK-8776

  • – GDC-0575

  • – PF00477736

  • – SCH 900776

 
GDC-0575: phase I with gemcitabine in advanced solid tumors and lymphoma 
  • – Chk1 overexpression suggests sensitivity

  • – RAD50 mutation reported in outlier response to Chk1 inhibitor + chemotherapy

 
  Chk1/Chk2 inhibitors:
  • – AZD7762

  • – LY2606368

 
LY2606368: phase II in breast, ovarian, and metastatic prostate cancer and small cell lung cancer  
  Chk2 inhibitors Preclinical  
p53 targeting Wee1 kinase is involved in G2-checkpoint signaling Wee1 inhibitor:
  • – AZD1775 (MK-1775)

 
AZD1775: phase I and II in advanced solid tumors and myeloid malignancies in combination with chemotherapy or PARPi TP53-mutant tumors are more sensitive because they lack the G1 checkpoint and rely on the G2 checkpoint for DNA repair 
CDK inhibitors  CDK4/6 inhibitors:
  • – Palbociclib (PD-0332991)

  • – Ribociclib (LEE011)

  • – Abemaciclib (LY2835219)

  • – G1T28

 
  • Palbociclib is FDA-approved.

  • Palbociclib, ribociclib, and abemaciclib in phase I-III trials as single agent or in combination with chemotherapy or targeted agents in various solid tumors.

  • – G1T28 is in phase I/II trials + chemotherapy in SCLC

 
– Loss of Rb and CCNE1 copy gains are associated with resistance to CDK4/6 inhibitors 
  Multiple CDK inhibitors:
  • – Dinaciclib (SCH-727965) (CDK1/2/5/9/12)

  • – AT7519 (CDK 1/2/4/5/6/9)

  • – SNS-032 (CDK2/7/9)

 
  • Dinaciclib: phase I/II alone or in combinations in solid tumors and hematologic cancers

  • AT7519: phase I/II in solid tumors and hematologic cancers

 
– CCNE1-amplified tumors may be sensitive to CDK2 inhibitors 
  CDK12 inhibitors Preclinical Under development 
ClassTarget protein role in DDRClasses of agents and examples of drugs in clinical trialsClinical development phase and contextPotential biomarkers
PARP inhibitors PARP detects single-strand DNA breaks and synthesizes a poly (ADP-ribose) chain (PAR) to recruit repair proteins PARP inhibitors:
  • – Olaparib

  • – Rucaparib

  • – Niraparib

  • – Veliparib

  • – Talazoparib

 
  • Olaparib: FDA-approved in recurrent ovarian cancer with germline BRCA1/2 mutations

  • Others in phase I–III trials in advanced solid malignancies, alone or in combination with chemotherapy, antiangiogenic agents, other targeted agents, and immunotherapy (Supplementary Table S1)

 
Assays for HRR deficiency (Table 2):
  • – Exome sequencing of HRR genes

  • – Mutational signatures

  • – Copy number analyses

  • – Gene and protein expression

  • – Functional assays

 
ATM/ATR inhibitors ATM/ATR: kinases that collaborate with Chk1/2 to arrest cell cycle, allowing time for DNA repair ATR inhibitors:
  • – VX-970

  • – AZD6738

 
VX-970, AZD6738: phase I/II trials combined with chemotherapy or radiation in advanced solid tumors 
  • ATR alterations

  • Alternative lengthening of telomeres

  • ATRX loss

  • DDR deficiency

  • Replication stress

 
  ATM inhibitor:
  • – AZD0156

 
Phase I trial ± PARPi in advanced malignancies 
  • ATM alterations

  • DDR deficiency

  • Replication stress

 
  ATM/ATR inhibitors Preclinical  
NHEJ inhibitors DNA-PK: enzyme complex initiating repair of DSBs by NHEJ (DNA-PKcs = catalytic subunit) DNA-PKcs inhibitors:
  • – CC-122

  • – ZSTK474

  • – CC-115

  • – MSC2490484A

  • – NU7026

  • – NU7441

 
  • MSC2490484A combined with radiation in an ongoing phase I trial

  • CC-115 and CC-122 in phase I trials in advanced malignancies

 
Under development 
 DNA ligase IV: major DNA ligase enzyme in NHEJ DNA ligase IV inhibitors Preclinical Under development 
BER inhibitors AP endonuclease 1 (APE-1) helps remove damaged bases in BER APE-1 inhibitors:
  • – Methoxyamine (TRC102)

  • – Inhibitors of AP endonuclease activity (e.g., lucanthone)

 
Phase I and II combinations with pemetrexed/cisplatin or temozolomide in advanced solid tumors HRR defects may increase sensitivity 
 Bifunctional polynucleotide phosphatase/kinase (PNKP) adds or removes phosphates to DNA ends; also involved in NHEJ PNKP inhibitors Preclinical Under development 
 DNA polymerase beta (POLβ) synthesizes DNA in BER POLβ inhibitors Preclinical Under development 
MRN complex inhibitors (HRR) MRN complex (MRE11A–RAD50– NBN) recognizes DSBs and initiates repair via protein recruitment; MRE11A mediates end resection MRE11 inhibitors (e.g., mirin) Preclinical Under development 
HRR inhibitors RAD51: recombinase promoting homologous recombination RAD51 inhibitors Preclinical Under development 
 DNA helicases unwind DNA in several repair processes Inhibitors of helicases (e.g., BLM, WRN, RECQL1) Preclinical Under development 
Chk1/2 inhibitors Chk1 and Chk2: cell-cycle checkpoint kinases. Chk1 promotes cell-cycle arrest at the G2–M checkpoint and DNA repair. Chk2 promotes the G1 checkpoint and DNA repair. Chk1 inhibitors:
  • – MK-8776

  • – GDC-0575

  • – PF00477736

  • – SCH 900776

 
GDC-0575: phase I with gemcitabine in advanced solid tumors and lymphoma 
  • – Chk1 overexpression suggests sensitivity

  • – RAD50 mutation reported in outlier response to Chk1 inhibitor + chemotherapy

 
  Chk1/Chk2 inhibitors:
  • – AZD7762

  • – LY2606368

 
LY2606368: phase II in breast, ovarian, and metastatic prostate cancer and small cell lung cancer  
  Chk2 inhibitors Preclinical  
p53 targeting Wee1 kinase is involved in G2-checkpoint signaling Wee1 inhibitor:
  • – AZD1775 (MK-1775)

 
AZD1775: phase I and II in advanced solid tumors and myeloid malignancies in combination with chemotherapy or PARPi TP53-mutant tumors are more sensitive because they lack the G1 checkpoint and rely on the G2 checkpoint for DNA repair 
CDK inhibitors  CDK4/6 inhibitors:
  • – Palbociclib (PD-0332991)

  • – Ribociclib (LEE011)

  • – Abemaciclib (LY2835219)

  • – G1T28

 
  • Palbociclib is FDA-approved.

  • Palbociclib, ribociclib, and abemaciclib in phase I-III trials as single agent or in combination with chemotherapy or targeted agents in various solid tumors.

  • – G1T28 is in phase I/II trials + chemotherapy in SCLC

 
– Loss of Rb and CCNE1 copy gains are associated with resistance to CDK4/6 inhibitors 
  Multiple CDK inhibitors:
  • – Dinaciclib (SCH-727965) (CDK1/2/5/9/12)

  • – AT7519 (CDK 1/2/4/5/6/9)

  • – SNS-032 (CDK2/7/9)

 
  • Dinaciclib: phase I/II alone or in combinations in solid tumors and hematologic cancers

  • AT7519: phase I/II in solid tumors and hematologic cancers

 
– CCNE1-amplified tumors may be sensitive to CDK2 inhibitors 
  CDK12 inhibitors Preclinical Under development 

NOTE: For purposes of this table, specific agents were listed only if they are in current or recent clinical trials, but numerous additional molecules have entered clinical or preclinical development over the past decade. Active clinical trials were identified from a keyword search of clinicaltrials.gov (April–May 2016) limited to United States, phase I/II/III, age >18, and open studies.

Several biomarkers for response to ATM or ATR inhibitors have been proposed, though clinical data are limited. Alterations in the target kinases (ATM/ATR) or their protein complexes may confer sensitivity to ATM and/or ATR inhibitors (66, 68). DDR deficiencies may sensitize to ATM/ATR inhibitors due to increased reliance on DDR checkpoints (68). Alterations causing increased replication stress may enhance sensitivity to ATM/ATR inhibition, for example, TP53 mutations, CCNE1 (Cyclin E1) amplifications (69, 70), and mutations in oncogenic drivers such as RAS and MYC (71, 72). Alternative lengthening of telomeres (ALT), the maintenance of telomere length through an HRR-based mechanism as an alternative to telomerase, may be a biomarker of hypersensitivity to ATR inhibitors (73). Loss of ATRX, a chromatin remodeling protein, was associated with increased ALT in most cell lines (73), and may also predict response to ATR inhibition.

NHEJ is a second major pathway of DSB repair, along with HRR. Repair pathway choice between NHEJ and HRR is mediated by cell-cycle phase (HRR occurs during S phase, whereas NHEJ can proceed during all phases) and by active mediators of pathway choice such as TP53BP1, which promotes HRR and inhibits NHEJ (4). NHEJ is more error prone due to its end processing and re-ligation mechanism resulting in nucleotide loss versus the conservative recombination of HRR using a normal DNA template to exactly replace the damaged region (1).

Inhibitors of several NHEJ proteins have been developed, and DNA-PKcs inhibitors are the most clinically advanced (Table 3; reviewed in refs. 74, 75). DNA-PKcs is the catalytic subunit of DNA-PK, a PI3K-related kinase similar to ATM and ATR. Phosphorylation of substrates by DNA-PK induces recruitment of repair proteins to DSBs and activation of checkpoints (75). CC-115 is a DNA-PKcs/mTOR inhibitor that has entered clinical trials (76), and CC-122 is a DNA-PK inhibitor (termed a “pleiotropic pathway modifier”) in a phase I clinical trial (75). ZSTK474 is an ATP-competitive inhibitor of PI3K that also inhibits DNA-PK and has been tested in early phase clinical trials (75). NU7026 and NU7441 are selective ATP-competitive inhibitors of DNA-PK undergoing preclinical development (77, 78). DNA-PK inhibitors sensitize cancer cells to DSB-inducing chemotherapies or radiation in preclinical studies, so combination strategies may be considered; MSC2490484A is a DNA-PK inhibitor being combined with radiotherapy in a phase I trial (Supplementary Table S1).

Biomarkers of sensitivity to NHEJ inhibition have not yet been validated, although in vitro HRR-deficient cells exhibit enhanced sensitivity to DNA-PK inhibition, perhaps because they are more dependent on NHEJ for repair of DSBs (1). Synthetic lethality between DNA-PK loss and various DDR proteins has been observed in preclinical studies (1, 79).

Several classes of DNA repair targeted agents have emerged in preclinical and early clinical studies (Table 3) that are outside the scope of this review, including inhibitors of AP endonuclease 1 (APE-1), bifunctional polynucleotide phosphatase/kinase (PNKP), DNA polymerase beta, RAD51, RAD52, and DNA repair associated helicases such as BLM. The checkpoint kinases Chk1 and Chk2 are intimately linked to the DNA-damage cell-cycle checkpoint mediated by ATM and ATR, and Chk1/Chk2 inhibitors are advancing in clinical trials (reviewed in refs. 2, 3, 80).

Several other classes of agents are closely linked to DDR, and many show enhanced activity in cells with DDR deficiencies. CDK inhibitors block cyclin-dependent kinases critical to cell-cycle progression, thereby impacting DNA repair that occurs during, and depends upon, specific phases of the cell cycle. These include inhibitors of CDK4/6 (e.g., palbociclib, which was recently FDA approved in metastatic breast cancer), CDK1/2/5/9, and CDK12. CDK12 promotes transcription of large RNAs including many HRR genes; inhibition of CDK12 has also been shown to downregulate HRR through transcriptional regulation (81, 82).

The p53 protein is critical to the DNA damage response via numerous functions, including activation of DDR, G1–S arrest to allow DNA repair, and apoptotic cell death following irreparable DNA damage. Wee1 inhibitors enhance sensitivity to DNA-damaging agents, preferentially in p53-deficient cells that are more reliant on the G2 checkpoint (83).

Biomarkers for most of these agents have yet to be determined (Table 3).

DNA repair targeted agents are rapidly affecting cancer therapy. PARP inhibitors have become the paradigm of synthetic lethality and are expanding therapeutic options in many cancer types, but the >1,000-fold increase in sensitivity seen in cells deficient for BRCA1 or BRCA2 has not been matched by other DNA repair therapies. Nevertheless, genomic sequencing has revealed a previously underappreciated frequency of DNA repair aberrations across tumor types, suggesting that many patients with advanced malignancies may be candidates for DNA repair targeted therapeutics.

Several issues need to be addressed to optimize the clinical application of DNA repair targeted agents. Robust and clinically feasible biomarkers of response and resistance must be developed, necessitating comprehensive incorporation of potential biomarkers in clinical trials, technical standardization of biomarker assays, and systematic clinical data collection to correlate biomarker data with clinical responses. Promising predictive biomarkers must then be tested prospectively; for instance, BRCA1/2 germline mutations were tested prospectively as biomarkers for PARPi response, and LOH-based HRR deficiency assays are embedded in ongoing PARPi trials. Additional research is required to identify and validate predictive biomarkers, particularly for DNA repair targeted therapies beyond PARPi, and, at some point, head-to-head comparisons will be required to compare biomarkers in situations where multiple tests are available. Finally, minimally invasive “blood biopsies” of circulating tumor cells or plasma cell-free DNA may contain sufficient genomic information to infer DDR phenotypes of solid tumors in the absence of a tissue biopsy (84); incorporating blood biopsies alongside tumor-based assays will allow rapid assessment of this promising biomarker strategy.

Optimal application of DNA repair targeted agents may require combination strategies (Supplementary Table S1). Maximizing the cellular dependency on DDR inhibition often requires a DNA damage insult, such as chemotherapy or radiation (3). Additionally, responses to DNA repair targeted agents may be enhanced by targeting alternative DDR pathways upon which cells rely when the canonical repair pathway is impaired, potentially resulting in increased efficacy from combinations of two or more DNA repair targeted agents. Some caution is warranted in combination strategies that result in simultaneous deficiencies in more than one DNA repair pathway (whether endogenous or pharmacologic), as they may have variable effects on drug sensitivity or resistance depending on the specific pathway or drug (e.g., MMR deficiencies are associated with either resistance or sensitivity to different chemotherapeutics; ref. 85).

Studies are also coupling DNA repair targeted agents with other classes of targeted drugs, including MAPK or PI3K inhibitors or antiangiogenic agents. For instance, combinations of PARP inhibitors with VEGFR inhibitors (e.g., olaparib/cediranib; ref. 86) are advancing in clinical trials, and PI3K inhibitors appear to sensitize to PARP inhibitors in several preclinical studies (87, 88).

Finally, cells deficient in certain DDR pathways (especially MMR and proofreading DNA polymerase epsilon, and probably HRR) may exhibit greater responsiveness to immunotherapy due to increased neoantigens as a consequence of high mutation frequencies (89–91). In cells lacking such defects, adding DNA repair targeted agents could increase endogenous DNA damage and enhance responses to immunotherapy. However, DNA repair deficiencies may have other unforeseen immunologic consequences, such as impaired antigen presentation in MMR-deficient cells with mutations in a microsatellite that ablates beta2-microglobulin (92). Combinations of PARPi plus immunotherapy targeting PD-1/PD-L1 are entering clinical trials (Supplementary Table S1).

Despite optimism for DNA repair targeted agents, some caution is in order. Treatment with DNA repair inhibitors could increase mutation rates in malignant cells, leading to evolution of metastatic properties and/or drug resistance. Systemic DNA damage could increase the risk of secondary malignancies. For example, myelodysplastic syndrome risk may increase with platinum and PARPi (93).

In summary, due to the fundamental reliance of cancer cells upon DDR pathways, DNA repair targeted agents represent an exciting group of emerging therapeutics with potential to improve outcomes across a variety of cancer types. Identification and validation of accurate biomarkers of response and resistance to DNA repair targeted agents will improve patient selection and increase the clinical value of DNA repair targeted therapy.

P.A. Konstantinopoulos is a consultant/advisory board member for Merck and Vertex Pharmaceuticals. U.A. Matulonis is a consultant/advisory board member for AstraZeneca, Clovis, Genentech/Roche, Immunogen, and Merck. E.M. Swisher is a consultant/advisory board member for IDEAYA Biosciences. No potential conflicts of interest were disclosed by the other author.

We apologize to authors whose work could not be included due to space constraints.

This work was supported by Department of Defense (DoD) grants OC093426 and DoD OC140632 (to P.A. Konstantinopoulos), DoD OC120506 (to E.M. Swisher), OCRFA Program Project Grant (to P.A. Konstantinopoulos), and a V Foundation Translational Research Award (to E.M. Swisher). Research also supported by a Stand Up To Cancer—Ovarian Cancer Research Fund Alliance—National Ovarian Cancer Coalition Dream Team Translational Research Grant (grant number: SU2C-AACR-DT16-15). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C (to E.M. Swisher, U.A. Matulonis, and P.A. Konstantinopoulos).

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