Reversion of pathogenic BRCA1 L1780P mutation confers resistance to PARP and ATM inhibitor in breast cancer.

ABSTRACT: This study investigates the molecular characteristics and therapeutic implications of the BRCA1 L1780P mutation, a rare variant prevalent among Korean hereditary breast cancer patients. Using patient-derived xenograft (PDX) models and cell lines (PDX-derived cell line) from carriers, sequencing analyses revealed loss of heterozygosity (LOH) at the BRCA1 locus, with one patient losing the wild-type allele and the other mutated allele. This reversion mutation may cf. resistance to homologous recombination deficiency (HRD)-targeting drugs such as PARP inhibitors (PARPi) and ATM inhibitors (ATMi). Although HRDetect and CHORD analyses confirmed a strong association between the L1780P mutation and HRD, effective initially, drug resistance developed in cases with reversion mutations. These findin

SUBMITTER: Jo SY 

PROVIDER: S-EPMC11326956 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature