Breast cancer PDX models with acquired resistance to olaparib: A preclinical platform to uncover mechanisms of PARP inhibitor escape

PARP inhibitors (PARPi), such as olaparib, have significantly improved the prognosis of breast cancer patients harboring BRCA1/2 mutations or with homologous recombination deficiency (HRD). However, the emergence of acquired resistance remains a major clinical obstacle. Robust preclinical models are therefore essential to elucidate the mechanisms of resistance and evaluate new therapeutic strategies. Within our cohort of 55 patient-derived breast cancer (PDX) xenografts, 51 were exposed in vivo to olaparib, of which 19 showed sensitivity. Several HRD models were then chronically treated with olaparib until tumor recurrence, indicating acquired resistance. Resistant tumors and their parental sensitive counterparts were comprehensively compared using histopathological, transcriptomic (RNA-seq), and genomic (whole-exome sequencing) analyses. To date, we have established a panel of nine olaparib-resistant derivatives from six initially sensitive PDX models through continuous in vivo exposure. These resistant models exhibit heterogeneous resistance mechanisms, including BRCA1 mutation reversion, partial restoration of homologous recombination, and overexpression of DNA repair pathways. Overall, this panel of olaparib-resistant PDX breast cancer models represents a valuable preclinical resource to investigate PARPi resistance mechanisms and to guide the development of second-line combination therapies for HRD breast cancer.