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

Key findings from this study

This research indicates that:

• BRN2-driven activation of ATR/RAD51 and STAT3 pathways confers acquired talazoparib resistance reversible by dual pathway inhibition in triple-negative breast cancer.
• HR repair-proficient subclones lacking SHLD2 expression can expand during talazoparib monotherapy despite initial tumor HR deficiency.
• Resistance mechanisms in the neoadjuvant setting include both pre-existing subpopulations and treatment-selected pathway activation not previously documented in this clinical context.

Overview

Triple-negative breast cancer with germline BRCA1/2 mutations frequently exhibits resistance to PARP inhibitor monotherapy in the neoadjuvant setting. This study identified distinct resistance mechanisms in treatment-naive and treated tumors from a phase II clinical trial of talazoparib monotherapy.

Methods and approach

Researchers analyzed tumor samples from patients with germline BRCA1/2 mutant breast cancers collected before and after six months of neoadjuvant talazoparib monotherapy. Whole-transcriptome analysis characterized both paired patient tissues and orthotopic patient-derived xenografts. Whole-exome sequencing supplemented transcriptomic data for xenograft samples. Mechanistic validation employed targeted inhibition of identified pathway components.

Results

Two distinct resistance pathways emerged from the integrated genomic and transcriptomic analysis. BRN2 overexpression in one tumor reactivated homologous recombination repair through ATR/RAD51 and STAT3 pathway activation, conferring talazoparib resistance reversible by combined ATR and STAT3 inhibition. In a second case, intrinsic resistance stemmed from clonal expansion of an HR repair-proficient subpopulation that lacked Shieldin 2 expression, present at baseline and enriched during treatment.

These findings represent both previously characterized PARP inhibitor resistance mechanisms and mechanisms not previously documented in the neoadjuvant context. The BRN2-mediated pathway demonstrates therapeutic vulnerability through dual targeting. The SHLD2-deficient subclone indicates that resistant populations may exist pre-treatment and require baseline tumor characterization for rational therapeutic design.

Implications

Genomic profiling of treatment-naive breast tumors may enable prospective identification of intrinsic resistance pathways and inform selection of combination strategies. BRN2-mediated resistance, reversible through ATR/STAT3 inhibition, suggests that combination PARPi regimens could overcome this acquired resistance mechanism. Detecting HR repair-proficient subclones before neoadjuvant therapy initiation could guide treatment decisions and improve patient stratification.

These observations support a paradigm shift toward multi-drug approaches in neoadjuvant PARP inhibitor therapy rather than single-agent monotherapy. Pretreatment tumor characterization may identify patients likely to benefit from combination strategies, potentially improving pathologic complete response rates. Future trial designs should incorporate systematic genomic analysis to validate these resistance mechanisms prospectively.

Scope and limitations

This summary is based on the study abstract and available metadata. It does not include a full analysis of the complete paper, supplementary materials, or underlying datasets unless explicitly stated. Findings should be interpreted in the context of the original publication.