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Resistance to neoadjuvant talazoparib in triple-negative breast cancer mediated by BRN2-induced ATR/STAT3 pathways or Shieldin 2 subclone expansion

ABSTRACT: Intrinsic and acquired resistance to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) remains a major barrier in treating homologous recombination (HR) repair-deficient tumors, including those with germline or somatic BRCA1/2 mutations. Although PARPi are FDA approved for adjuvant treatment of locally advanced or metastatic breast cancer in patients with germline BRCA1/2 mutations, emerging data support their use as monotherapy in the neoadjuvant setting. Promising safety profiles of newer-generation PARPi further support this potential. However, resistance mechanisms specific to the neoadjuvant setting are poorly understood. To address this gap, we leveraged resources from a phase II neoadjuvant clinical trial (NCT03499353), analyzing tumors from patients with germline BRCA1/2 mutant breast tumors before and after six months of talazoparib monotherapy. Whole-transcriptome analyses were performed on these samples. Additionally, we established orthotopic patient-derived xenograft models from a subset of the patient tumors and conducted whole-exome and whole-transcriptome analysis. This integrative approach revealed both known and novel PARPi resistance mechanisms. In one case, overexpression of BRN2, encoding a transcription factor that plays a critical role in neurogenesis, led to activation of ATR/RAD51 and STAT3 pathways, restoring homologous recombination (HR) repair. BRN2-driven resistance could be reversed with ATR and STAT3 inhibitors, resensitizing cells to talazoparib. In another, an HR repair proficient tumor subclone lacking Shieldin 2 expression expanded during treatment and accounted for intrinsic resistance. Our findings highlight the need to determine intrinsic and anticipate acquired resistance pathways in treatment-naïve tumors and support combining PARPi with targeted agents to improve outcomes in the neoadjuvant setting.

ORGANISM(S): Homo sapiens

PROVIDER: GSE298644 | GEO | 2026/03/24

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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Resistance to neoadjuvant talazoparib in triple-negative breast cancer mediated by BRN2-induced ATR/STAT3 pathways or Shieldin 2 subclone expansion

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