Alterations in DNA damage response (DDR) genes are common in advanced prostate tumors and are associated with unique genomic and clinical features. ATM is a DDR kinase that has a central role in coordinating DNA repair and cell-cycle response following DNA damage, and ATM alterations are present in approximately 5% of advanced prostate tumors. Recently, inhibitors of PARP have demonstrated activity in advanced prostate tumors harboring DDR gene alterations, particularly in tumors with BRCA1/2 alterations. However, the role of alterations in DDR genes beyond BRCA1/2 in mediating PARP inhibitor sensitivity is poorly understood. To define the role of ATM loss in prostate tumor DDR function and sensitivity to DDR-directed agents, we created a series of ATM-deficient preclinical prostate cancer models and tested the impact of ATM loss on DNA repair function and therapeutic sensitivities. ATM loss altered DDR signaling, but did not directly impact homologou recombination function. Furthermore, ATM loss did not significant ly impact sensitivity to PARP inhibition but robustly sensitized t inhibitors of the related DDR kinase ATR. These results hav important implications for planned and ongoing prostate cance clinical trials and suggest that patients with tumor ATM alteration may be more likely to benefit from ATR inhibitor than PAR inhibitor therapy.
Bibliographical noteFunding Information:
This work was supported by grants DF/HCC Prostate SPORE (to K.W. Mouw), PCF Young Investigator Award (to K.W, Mouw), 5K08CA219504 (to K.W. Mouw), NCI PCF-V Foundation Challenge Award (to E.M. Van Allen), U01 CA233100 (to E. M. Van Allen), and U01 CA176058 (to W.C. Hahn).
A.D. Choudhury is an advisory board member at Clovis, Dendreon, and Bayer and reports receiving a commercial research grant from Bayer. W.C. Hahn is a scientific advisory board member at Thermo Fisher, KSQ Therapeutics, iTeos, Frontier Medicine, Tyra Biosciences, Solvanta, and MPM, reports receiving a commercial research grant from Deerfield, and has ownership interest (including patents) in Frontier Medicines, KSQ Therapeutics, and Tyra Biosciences. E.M. Van Allen is a consultant at Tango Therapeutics, Ervaxx, Genome Medical, Invitae, and Janssen, reports receiving a commercial research grant from BMS, Novartis, and has ownership interest (including patents) in Genome Medical, Tango Therapeutics, Ervaxx, and Synapse. K.W. Mouw is an advisory board member at Pfizer and EMD Serono and reports receiving a commercial research grant from Pfizer. No potential conflicts of interest were disclosed by the other authors.
© 2020 American Association for Cancer Research.