Clinical homologous recombination repair gene reversion analysis identifies mechanisms of resi stance to PARP inhibitors and platinum-chemotherapy

Abstract

Identifying mechanisms underlying cancer resistance to therapy is vital for advancing treatment strategies. Pathogenic mutations of homologous recombination repair (HRR) genes are known biomarkers for platinum (Pt)-based chemotherapy and poly ADP ribose polymerase inhibitors (PARPi) effectiveness. Yet, the dynamics of HRR reversion mutations, which may herald therapy resistance, are not fully elucidated. Addressing this gap, our study analyzed secondary HRR gene mutations in a comprehensive pancancer data set of approximately 13,000 patients who underwent targeted nextgeneration sequencing. We identified a subset of patients harboring secondary mutations, which were further categorized into three tiers based on their nature, and occur in the presence of a primary pathogenic mutation, notably in BRCA1, BRCA2, PALB2, and RAD51D genes. Here we show that secondary BRCA2 mutations, indicative of adaptive resistance, emerge post-Pt/Olaparib treatment. This challenges the prevailing notion that pathogenic HRR mutations uniformly predict therapeutic sensitivity, highlighting a nuanced genetic interplay that impacts treatment success. This investigation enriches our understanding of cancer’s adaptive mechanisms against therapy, suggesting a pivotal shift towards more personalized, dynamic treatment strategies. It underscores the imperative of adapting to cancer’s genetic evolution, aiming for a step ahead in the ongoing battle against this disease.

Keywords

drug resistance / homologous recombination repair / PARP inhibitor / platinumchemotherapy / reversion mutation

RIGHTS & PERMISSIONS

2024 The Authors. MedComm – Oncology published by John Wiley & Sons Australia, Ltd on behalf of Sichuan International Medical Exchange & Promotion Association (SCIMEA).