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Investigating response to PARP inhibition and androgen receptor pathway inhibition in C4-2B prostate cancer cells

ABSTRACT: Use of PARP inhibitors (PARPi) has been shown effective in the management of selected patients with advanced prostate cancer. Still, it is incompletely understood how PARPi work and what mechanisms may enable adaptation and progression. This study utilized RNA-sequencing to understand response to PARP inhibition (olaparib) in regard to both intensity and duration of treatment. PARPi have also been shown to be effective when combined with androgen receptor (AR) pathway inhibitors (ARPi), but much remains unknown regarding the utility of combination regimens. We additionally performed RNA-sequencing to better define transcriptomic changes associated with either monotherapy PARPi (olaparib or talazoparib), monotherapy ARPi (abiraterone or enzalutamide), or combinations (abiraterone + olaparib, enzalutamide + talazoparib).

ORGANISM(S): Homo sapiens

PROVIDER: GSE322615 | GEO | 2026/06/03

REPOSITORIES: GEO

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Project description:Background: PARP inhibition (PARPi) has demonstrated potent therapeutic efficacy in patients with BRCA-mutant ovarian cancer. However, acquired resistance to PARPi remains a major challenge in the clinic. Methods: PARPi-resistant ovarian cancer mouse models were generated by long-term treatment of olaparib in syngeneic Brca1-deficient ovarian tumors. STAT3-mediated immunosuppression was investigated in vitro by co-culture experiments and in vivo by analysis of immune cells in the TME of human and mouse PARPi-resistant tumors. Whole genome transcriptome analysis was performed to assess the anti-tumor immunomodulatory effect of STING (stimulator of interferon genes) agonists on myeloid cells in the TME of PARPi-resistant ovarian tumors. A STING agonist was used to overcome STAT3-mediated immunosuppression and acquired PARPi resistance in syngeneic and PDX models of ovarian cancer. Results: In this study, we uncover an adaptive resistance mechanism to PARP inhibition mediated by tumor associated macrophages (TAMs) in the tumor microenvironment (TME). Markedly increased populations of pro-tumor macrophages are found in BRCA-deficient ovarian tumors that rendered resistance to PARPi in both murine models and patients. Mechanistically, PARP inhibition elevates the STAT3 signaling pathway in tumor cells, which in turn promotes pro-tumor polarization of TAMs. STAT3 ablation in tumor cells mitigates polarization of pro-tumor macrophages and increases tumor-infiltrating T-cells upon PARP inhibition. These findings are corroborated in patient-derived, PARPi-resistant BRCA1-mutant ovarian tumors. Importantly, STING agonists reshape the immunosuppressive TME by reprogramming myeloid cells and overcome the TME-dependent adaptive resistance to PARPi in ovarian cancer. This effect is further enhanced by addition of PD-1 blockade. Conclusions: We elucidate an adaptive immunosuppression mechanism rendering resistance to PARPi in BRCA1-mutant ovarian tumors. This is mediated by enrichment of pro-tumor TAMs propelled by PARPi-induced STAT3 activation in tumor cells. We also provide a new strategy to reshape the immunosuppressive TME with STING agonist and overcome PARPi resistance in ovarian cancer.

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Investigating response to PARP inhibition and androgen receptor pathway inhibition in C4-2B prostate cancer cells

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