Resistance to neoadjuvant talazoparib in triple-negative breast cancer by BRN2-induced ATR/STAT3 pathways or SHLD2 subclone expansion

Clinical Snapshot

Key Findings

• P Value: Not reported

• Effect Size: Not quantified in abstract

• Primary Outcome: Identification of BRN2-mediated ATR/STAT3 pathway activation and SHLD2 subclone expansion as resistance mechanisms

• Nnt Or Sensitivity: Resistance reversal achieved with ATR and STAT3 inhibitor combinations

• Confidence Interval: Not reported

Clinical Application

Requires molecular profiling capabilities and access to combination targeted therapies Relevant to Australian practice where talazoparib is PBS-listed for BRCA-mutant breast cancer; findings support molecular testing strategies and combination therapy development Patients with germline BRCA1/2 mutant triple-negative breast cancer considering neoadjuvant PARP inhibitor therapy

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 previously unknown 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 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.

References

1. 1.Abdulkareem, N. M., Jiang, Y., Qi, Y., Liu, X., Zhang, X., Cai, S., Shao, J., Jeter-Jones, S., Rinkenbaugh, A. L., Cheng, C.-C., Hancock, F., Schwartz, J., Litton, J. K., Chang, J. T., & Piwnica-Worms, H. (2026). Resistance to neoadjuvant talazoparib in triple-negative breast cancer by BRN2-induced ATR/STAT3 pathways or SHLD2 subclone expansion. Proceedings of the National Academy of Sciences, 123, Article 2513742123. https://doi.org/10.1073/pnas.2513742123