Abstract
Pharmacological inhibition of the ataxia telangiectasia and Rad3-related protein serine/threonine kinase (ATR; also known as FRAP-related protein (FRP1)) has emerged as a promising strategy for cancer treatment that exploits synthetic lethal interactions with proteins involved in DNA damage repair, overcomes resistance to other therapies and enhances antitumour immunity. Multiple novel, potent ATR inhibitors are being tested in clinical trials using biomarker-directed approaches and involving patients across a broad range of solid cancer types; some of these inhibitors have now entered phase III trials. Further insight into the complex interactions of ATR with other DNA replication stress response pathway components and with the immune system is necessary in order to optimally harness the potential of ATR inhibitors in the clinic and achieve hypomorphic targeting of the various ATR functions. Furthermore, a deeper understanding of the diverse range of predictive biomarkers of response to ATR inhibitors and of the intraclass differences between these agents could help to refine trial design and patient selection strategies. Key challenges that remain in the clinical development of ATR inhibitors include the optimization of their therapeutic index and the development of rational combinations with these agents. In this Review, we detail the molecular mechanisms regulated by ATR and their clinical relevance, and discuss the challenges that must be addressed to extend the benefit of ATR inhibitors to a broad population of patients with cancer.
Key points
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Ataxia telangiectasia and Rad3-related protein serine/threonine kinase (ATR) has crucial and pleiotropic functions in the replication stress response. Small-molecule ATR inhibitors are actively being evaluated in the clinic for their single-agent activity, in rationally selected combinations, and for their capacity to overcome therapeutic resistance or promote antitumour immunity.
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Currently available data from clinical trials of single-agent ATR inhibitors have revealed an emerging efficacy signal in patients with ovarian cancers resistant to platinum-based chemotherapy and/or poly(ADP-ribose) polymerase (PARP) inhibitors, most of whom had been heavily pretreated. Preclinical and clinical data suggest that ATR inhibitors have the potential to overcome resistance to PARP inhibitors.
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The development of ATR inhibitors has been challenged by a narrow therapeutic index, mainly limited by dose-dependent myelosuppression, particularly anaemia. Intermittent dosing schedules could maximize target engagement while allowing sufficient time for erythroid precursor maturation and recovery.
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Interesting and rational combinatorial partners for ATR inhibitors are increasingly being discovered, although optimizing the toxicity profile and therapeutic window of ATR inhibitors in such combinations remains a challenge, in particular with drug partners that share overlapping haematological toxicities.
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No single integral biomarker of response to ATR inhibitors as monotherapy or in combination has been established to date; potential biomarkers include individual genomic alterations that predispose to replication stress accumulation, gene signatures indicating elevated replication stress and functional measures of replication stress.
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Acknowledgements
K.S. receives support from the Cancer Prevention and Research Institute of Texas (RP180813) and the National Institute of Health (NIH) (1R01ES029680), and is a CPRIT scholar in Cancer Biology and a Rita Allen Foundation Fellow. T.A.Y. receives support from the Department of Defense (W81XWH-21-1-0282 and W81XWH-22-1-0502) and the NIH (1R01CA255074), and is a V Foundation Scholar (VC2020-001).
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N.Y.L.N., P.G.P., D.J.M., K.S. and T.A.Y. researched data for the article. All the authors contributed substantially to discussion of the content, wrote the article, and reviewed and/or edited the manuscript before submission.
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P.G.P. and D.J.M. are involved in a pending patent related to a replication stress response deficiency signature. M.Z. is an employee of Repare Therapeutics. T.A.Y. is Vice President and Head of Clinical Development in the Therapeutics Discovery Division at University of Texas MD Anderson Cancer Center, which has a commercial interest in DDR and other inhibitors; receives institutional research support funded by Acrivon, Artios, AstraZeneca, Bayer, Beigene, BioNTech, Blueprint, BMS, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GSK, Genentech, Haihe, Ideaya, ImmuneSensor, Ionis, Ipsen, Jounce, Karyopharm, KSQ, Kyowa, Merck, Mirati, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Rubius, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, Vivace and Zenith; is a consultant for AbbVie, AstraZeneca, Acrivon, Adagene, Aduro, Almac, Amphista, Artios, Athena, Atrin, Avoro, Axiom, Baptist Health Systems, Bayer, Beigene, Boxer, BMS, C4 Therapeutics, Calithera, Cancer Res. UK, Clovis, Cybrexa, Diffusion, EMD Serono, F-Star, Genmab, Glenmark, GLG, Globe Life Sciences, GSK, Guidepoint, Idience, Ignyta, I-Mab, ImmuneSensor, Impact, Institut Gustave Roussy, Intellisphere, Jansen, Kyn, MEI Pharma, Mereo, Merck, Natera, Nexys, Novocure, OHSU, OncoSec, Ono Pharma, Pegascy, PER, Pfizer, Piper Sandler, Prolynx, Repare, resTORbio, Roche, Schrodinger, Theragnostics, Varian, Versant, Vibliome, Xinthera, Zai Labs and ZielBio; and holds stock from Seagen. N.Y.L.N. and K.S. declare no competing interests.
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Ngoi, N.Y.L., Pilié, P.G., McGrail, D.J. et al. Targeting ATR in patients with cancer. Nat Rev Clin Oncol 21, 278–293 (2024). https://doi.org/10.1038/s41571-024-00863-5
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DOI: https://doi.org/10.1038/s41571-024-00863-5
