TY - JOUR
T1 - ATR inhibition induces CDK1-SPOP signaling and enhances anti-PD-L1 cytotoxicity in prostate cancer
AU - Tang, Zhe
AU - Pilié, Patrick G.
AU - Geng, Chuandong
AU - Manyam, Ganiraju C.
AU - Yang, Guang
AU - Park, Sanghee
AU - Wang, Daoqi
AU - Peng, Shan
AU - Wu, Cheng
AU - Peng, Guang
AU - Yap, Timothy A.
AU - Corn, Paul G.
AU - Broom, Bradley M.
AU - Thompson, Timothy C.
N1 - Funding Information:
We acknowledge the editorial assistance of Sarah E. Townsend. This research was supported by MD Anderson NCI Prostate Cancer SPORE grant P50 CA140388, the NCI Cancer Center Support grant P30 CA16672, and a Young Investigator’s Award from the Prostate Cancer Foundation (to P.G. Pilié).
Funding Information:
P.G. Piliéreports grants from Prostate Cancer Foundation and ASCO Career Development Award during the conduct of the study, as well as a patent for Replication Stress Response Biomarker pending. T.A. Yap reports grants from Artios, Constellation, Cyteir, Eli Lilly, Forbius, GlaxoSmithKline, Genentech, Immune Sensor, Ipsen, Jounce, Karyopharm, Kyowa, Novartis, Ribon Therapeutics, Regen-eron, Sanofi, Scholar Rock, Tesaro, and Vertex Pharmaceuticals; grants and personal fees from AstraZeneca, Bayer, Clovis, EMD Serono, F-Star, Merck, Pfizer, Repare, and Seattle Genetics; and personal fees from Almac, Aduro, Atrin, Axiom, Bristol Myers Squibb, Calithera, Cybrexa, Guidepoint, Ignyta, I-Mab, Janssen, Roche, Rubius, Schrodinger, Varian, and Zai Labs outside the submitted work. T.C. Thompson reports grants from Bayer Healthcare Pharmaceuticals, Inc. outside the submitted work. No disclosures were reported by the other authors.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/9/1
Y1 - 2021/9/1
N2 - Purpose: Despite significant benefit for other cancer subtypes, immune checkpoint blockade (ICB) therapy has not yet been shown to significantly improve outcomes for men with castration-resistant prostate cancer (CRPC). Prior data have shown that DNA damage response (DDR) deficiency, via genetic alteration and/or pharmacologic induction using DDR inhibitors (DDRi), may improve ICB response in solid tumors in part due to induction of mitotic catastrophe and innate immune activation. Discerning the underlying mechanisms of this DDRi-ICB interaction in a prostate cancer-specific manner is vital to guide novel clinical trials and provide durable clinical responses for men with CRPC. Experimental Design: We treated prostate cancer cell lines with potent, specific inhibitors of ATR kinase, as well as with PARP inhibitor, olaparib. We performed analyses of cGAS-STING and DDR signaling in treated cells, and treated a syngeneic androgenindifferent, prostate cancer model with combined ATR inhibition and anti-programmed death ligand 1 (anti-PD-L1), and performed single-cell RNA sequencing analysis in treated tumors. Results: ATR inhibitor (ATRi; BAY1895433) directly repressed ATR-CHK1 signaling, activated CDK1-SPOP axis, leading to destabilization of PD-L1 protein. These effects of ATRi are distinct from those of olaparib, and resulted in a cGAS-STING-initiated, IFN-β-mediated, autocrine, apoptotic response in CRPC. The combination of ATRi with anti-PD-L1 therapy resulted in robust innate immune activation and a synergistic, T-cell-dependent therapeutic response in our syngeneic mouse model. Conclusions: This work provides a molecular mechanistic rationale for combining ATR-targeted agents with immune checkpoint blockade for patients with CRPC. Multiple early-phase clinical trials of this combination are underway.
AB - Purpose: Despite significant benefit for other cancer subtypes, immune checkpoint blockade (ICB) therapy has not yet been shown to significantly improve outcomes for men with castration-resistant prostate cancer (CRPC). Prior data have shown that DNA damage response (DDR) deficiency, via genetic alteration and/or pharmacologic induction using DDR inhibitors (DDRi), may improve ICB response in solid tumors in part due to induction of mitotic catastrophe and innate immune activation. Discerning the underlying mechanisms of this DDRi-ICB interaction in a prostate cancer-specific manner is vital to guide novel clinical trials and provide durable clinical responses for men with CRPC. Experimental Design: We treated prostate cancer cell lines with potent, specific inhibitors of ATR kinase, as well as with PARP inhibitor, olaparib. We performed analyses of cGAS-STING and DDR signaling in treated cells, and treated a syngeneic androgenindifferent, prostate cancer model with combined ATR inhibition and anti-programmed death ligand 1 (anti-PD-L1), and performed single-cell RNA sequencing analysis in treated tumors. Results: ATR inhibitor (ATRi; BAY1895433) directly repressed ATR-CHK1 signaling, activated CDK1-SPOP axis, leading to destabilization of PD-L1 protein. These effects of ATRi are distinct from those of olaparib, and resulted in a cGAS-STING-initiated, IFN-β-mediated, autocrine, apoptotic response in CRPC. The combination of ATRi with anti-PD-L1 therapy resulted in robust innate immune activation and a synergistic, T-cell-dependent therapeutic response in our syngeneic mouse model. Conclusions: This work provides a molecular mechanistic rationale for combining ATR-targeted agents with immune checkpoint blockade for patients with CRPC. Multiple early-phase clinical trials of this combination are underway.
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U2 - 10.1158/1078-0432.CCR-21-1010
DO - 10.1158/1078-0432.CCR-21-1010
M3 - Article
C2 - 34168048
AN - SCOPUS:85114190966
SN - 1078-0432
VL - 27
SP - 4898
EP - 4909
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 17
ER -