ATR Inhibition as an Attractive Therapeutic Resource against Cancer

The DNA damage response (DDR) network is made of a highly organized system of proteins which are able to identify DNA damage and to induce various biological processes, including the activation of checkpoint, which puts the cell cycle on pause, DNA repair, and cell apoptosis. DDR, therefore, plays a crucial role in protecting the genome from accumulating endogenous and environmental DNA damage.

Ataxia telangiectasia and Rad3-related (ATR) is a member of the PI3K-like family of kinases, which include ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase catalytic subunit (1), other key actors of the DDR. ATR is recruited to regions of single-stranded DNA within double-stranded DNA. Once activated, ATR phosphorylates several substrates, particularly CHK1. This signaling cascade regulates key cell functions, including the arrest of cell cycle by activation of intra-S-phase and G₂–M-phase checkpoints, regulation of origin firing, stabilization of replication forks, and the repair of DNA damage (2).

Defects in the DDR are common in cancer, resulting in a decreased ability of many cancers cells to repair DNA lesions in comparison with normal cells. The majority of the cytotoxic agents used routinely by medical oncologists rely on exploitation of these defects. Because several of these chemotherapy drugs induce an activation of ATR, it has long been considered a potential therapeutic target. This has been reinforced by several studies demonstrating that ATR inhibition could be tolerated by noncancer cells (3–5).

The first ATR inhibitors that were identified, such as caffeine (6), wortmannin (7), or schisandrin B (8), lacked potency and/or specificity. Indeed, the development of highly potent and specific inhibitors of ATR was challenged by the very large size of this protein, which required several high-throughput screens and important chemistry efforts.

In this issue of Cancer Discovery, Yap and colleagues report on the phase I, dose-escalation study evaluating the oral ATR inhibitor BAY 1895344 in patients with selected solid tumors (9). Briefly, 22 patients with advanced solid tumors were enrolled in this phase I trial (mainly patients with breast, colorectal, or prostate cancer). The majority of them were heavily pretreated with at least four prior lines of therapy.

Fifteen of them had alterations of the DDR pathway, including 11 patients with ATM alterations as a result of mutation and/or loss of expression and 4 patients with BRCA1 or BRCA2 mutation.

The authors demonstrated that BAY 1895344 can be safely administered to patients with cancer with an MTD of 40 mg twice a day in a 3 days on/4 days off schedule. Indeed, with a median duration of exposure of 64.5 days (range, 8–472), BAY 1895344 was well tolerated. Grade 3 treatment-related adverse events occurred in up to 80% of patients, but were mainly hematologic and most frequently observed at doses higher than the MTD, except for anemia.

With regard to efficacy, BAY 1895344 demonstrated durable clinical activity. Among the 13 patients eligible for the efficacy analysis, who received the MTD dose of BAY 1895344 or above, the objective response rate (ORR) was 30.8%. Three of the 4 patients with a RECIST partial response were still ongoing, with a time on treatment exceeding 1 year.

Strikingly, gene sequencing and protein expression analysis of the baseline tumor samples revealed ATM aberrations in all 4 patients with a RECIST partial response. An ORR of 33.3% (3/9 patients) was observed in patients with ATM protein loss across different dose levels and an ORR of 37.5% (3/8 patients) was observed in patients with ATM mutations.

To investigate the effect of BAY 1895344 on DNA damage, sequential tumor biopsies were obtained at baseline and on treatment from 17 patients enrolled in this dose-escalation study. Analysis of such biopsies showed that γH2AX levels increased on treatment with BAY 1895344, indicating that ATR kinase inhibition induces DNA damage by abrogation of DDR signaling

ATR and ATM share several substrates, and both of them phosphorylate proteins that are involved in DNA replication, recombination, and repair, and cell-cycle regulation in response to double-strand breaks (ref. 2; Fig. 1). The results of this study represent a clear clinical confirmation that defects in ATM pathway signaling can confer sensitivity to single-agent ATR inhibition, as suggested more than 20 years ago by preclinical studies (10).

Interestingly, ATR inhibition may also represent a relevant therapeutic approach in tumors that concurrently carry defects elsewhere in the DNA-repair network. For instance, defects in homologous recombination repair have also been associated with marked sensitivity to ATR inhibitors, as reported in a preclinical study showing the high sensitivity of BRCA2-defective cells to such agents (11). Interestingly, 1 of the patients included in the study reported by Yap and colleagues was diagnosed with a BRCA1 deleterious mutation and had durable clinical benefit from BAY 1895344, paving the way to a combinatorial approach with PARP inhibitors (9).

Although ATR inhibition may have significant clinical activity in well-defined cancer populations, the potential impact of this new class of agents may be enhanced by developing combination regimens.

In the discussion section of this study, the authors indicated their concerns related to the risk of hematologic toxicity if BAY 1895344 were to be combined with chemotherapy. However, adverse events, such as anemia, neutropenia, or thrombocytopenia, are side effects that medical oncologists are used to and comfortable managing. Given the strong synergy observed in several preclinical models when ATR inhibitors are combined with cytotoxic drugs (12), ATR inhibitors combined with chemotherapy represent an exciting novel therapeutic approach. This has been recently illustrated by the first randomized study investigating an ATR inhibitor in solid tumors that showed a statistically significant improvement in outcome in a population of patients with ovarian cancer treated with the specific ATR inhibitor M6620 combined with gemcitabine versus gemcitabine alone (13).

Combination with immuno-oncology agents may also represent another potentially interesting approach. Indeed, the role of DDR inhibitors as immunomodulatory agents that may synergize with immune checkpoint inhibitors has recently emerged. Recent preclinical evidence suggests that ATR inhibitors exhibit immunomodulatory functions and enhance antitumor efficacy of immune checkpoint therapy. For instance, BAY 1895344 has been shown to be synergistic with anti–PD-1 or anti–PD-L1 antibody in several syngeneic tumor models in immunocompetent mice, and depletion of CD8⁺ T cells strongly reduced its single-agent activity (14). Along this line, combination of the selective ATR inhibitor M6620 with the PD-L1 antagonist avelumab and platinum-based chemotherapy resulted in an antitumor effect in syngeneic tumor models, leading to overall survival benefit compared with any dual combination group, and also provided protective antitumor immunity with immunologic memory in cured mice (15). Interestingly, Yap and colleagues, by analyzing paired tumor biopsies of the patients included in this phase I study, found a significant increase of CD8 T-cell infiltration and an upregulation of PD-L1 expression in a subset of patients, suggesting an impact of BAY 1895344 on the tumor microenvironment even if the sample size was too small to make definitive conclusions.

Overall, the study reported by Yap and colleagues is an excellent illustration of how modern early-phase studies have to be conducted, that is, by matching an innovative drug with patients selected on the basis of specific molecular features. The results presented here pave the way for an exciting development of a new generation of DDR-targeting agents. Further efforts are needed to identify efficient and safe combinations of BAY 1895344 without neglecting the high synergistic potential of combination with conventional cytotoxic drugs.

A. Italiano reports grants and personal fees from Bayer, Merck, and Ipsen, grants from Roche, MSD, and AstraZeneca, grants and nonfinancial support from Epizyme and Novartis, and personal fees from SpringWorks outside the submitted work. No other disclosures were reported.