ArticleClinical cancer research : an official journal of the American Association for Cancer Research2021
ATR Inhibition Induces CDK1-SPOP Signaling and Enhances Anti-PD-L1 Cytotoxicity in Prostate Cancer.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 97 papers, 1 of them a synthesis that pooled it.
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Who cites it
97 citing papers in PubMed, 1 synthesis or guideline pooled it, 139 citations in OpenAlex.
- The efficacy and safety of ATR inhibitors in the treatment of solid tumors: a systematic review and meta-analysis.Frontiers in oncology · 2025Pooled it
- Phase II study of olaparib and durvalumab in patients with metastatic castration-resistant prostate cancer.Journal for immunotherapy of cancer · 2026Trial
- Not only as a Cullin3 ligase adaptor, SPOP may also act as a molecular bridge.Genes & diseases · 2027Review
- Targeted inhibition of ATR kinase promotes antitumor immunity in HNSCC through enhanced STING activation and T cell function.Translational oncology · 2026Article
- The DNA damage response and cancer immunotherapy.Nature reviews. Cancer · 2026Review
- The role of the cGAS-STING pathway in male reproductive disorders.Molecular biology reports · 2026Review
- Molecular insights for the tumor suppressor role of SPOP in prostate cancer.Biochimica et biophysica acta. Reviews on cancer · 2026Review
- X-ray preactivated reversible persistent luminescence enables photodynamic immunotherapy of deep tumors.Nature communications · 2026Article
- Dynamic reprogramming of the tumor immune network via multicycle checkpoint degradation for cancer immunotherapy.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Targeting PKMYT1 enhances antitumor immune responses to PD-L1 blockade in castration-resistant prostate cancer.Journal for immunotherapy of cancer · 2026Article
- Paroxetine repurposing enhances antitumor immunity via SPOP-mediated PD-L1 ubiquitination and proteasomal degradation.Journal of experimental & clinical cancer research : CR · 2026Article
- Next Generation DNA Damage Response Inhibitors: Harnessing Nanocarriers and Tumor Microenvironment for Precision Cancer Therapy.Oncology research · 2026Review
- Construction and verification of a prognostic model for prostate cancer based on ribosome biogenesis-related genes.BMC medical genomics · 2025Article
- The ATR inhibitor tuvusertib (M1774) sensitizes prostate carcinoma to natural killer cell-mediated cytotoxicity, which is further augmented by the IL-15 receptor superagonist N-803.Cancer immunology, immunotherapy : CII · 2025Article
- TFE3 fusion proteins promoted the progression of Xp11.2 translocation renal cell carcinoma through post-translational modification of PDL1 by upregulating CCND1/Cyclin D1.Cellular oncology (Dordrecht, Netherlands) · 2025Article
- Aurora kinase B phosphorylates ZBP1 to drive PANoptosis following treatment with PARP and ATR inhibitors combination.Nature communications · 2025Article
- Resilience and Vulnerabilities of Tumor Cells under Purine Shortage Stress.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- TLL1 knockdown attenuates prostate cancer progression by enhancing antitumor immunity.Oncogene · 2025Article
- Review
- Tumor irradiation induced immunogenic response: the impact of DNA damage induction and misrepair.Radiation oncology (London, England) · 2025Review
37 more citing papers are in PubMed but not listed here.
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Authors and funding
14 authors at 1 institution in 1 country.
Funding
Abstract
purposeDespite 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
designWe 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 androgen-indifferent, 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.
resultsATR 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.
conclusionsThis 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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.