ATR inhibition induces CDK1-SPOP signaling and enhances anti-PD-L1 cytotoxicity in prostate cancer

Zhe Tang, Patrick G. Pilié, Chuandong Geng, Ganiraju C. Manyam, Guang Yang, Sanghee Park, Daoqi Wang, Shan Peng, Cheng Wu, Guang Peng, Timothy A. Yap, Paul G. Corn, Bradley M. Broom, Timothy C. Thompson

Research output: Contribution to journalArticlepeer-review

57 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4898-4909
Number of pages12
JournalClinical Cancer Research
Volume27
Issue number17
DOIs
StatePublished - Sep 1 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

MD Anderson CCSG core facilities

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  • Advanced Technology Genomics Core
  • Cytogenetics and Cell Authentication Core
  • Flow Cytometry and Cellular Imaging Facility
  • Research Animal Support Facility

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