RAD51 Linked With PARP Inhibitor Resistance in BRCA-Mutated Breast Cancer

A biomarker known as RAD51 was found to be correlated with resistance to PARP inhibitor treatment in a study of breast cancer that harbors BRCA mutations. The marker could eventually be used to better select patients for treatment with these agents.

BRCA1- and BRCA2-deficient breast tumors display impaired homologous recombination repair (HRR), and defective HRR can increase the sensitivity of those tumors to various types of therapy, including PARP inhibitors. “Primary resistance to PARP inhibitors in a subset of [germline BRCA1/2 mutation carriers] limits the potential of BRCA status as the only biomarker of response to that of an enrichment strategy,” wrote study authors led by Violeta Serra, PhD, of the Vall d’Hebron Institute of Oncology in Barcelona.

Previous work has shown that induction of the nuclear foci of RAD51, an HRR protein, after neoadjuvant chemotherapy could be a measure of HRR functionality and can predict treatment response. The new work investigated a connection between RAD51 and PARP inhibitor resistance in the setting of BRCA-mutated breast cancer. The results were published in Annals of Oncology.

The researchers used an in vivo model of PARP inhibitor resistance in patient-derived tumor xenografts (PDXs). They used exome sequencing and immunostaining of DNA damage response proteins in order to evaluate HRR, and findings were then validated in a cohort of breast cancer patients with BRCA1/2 mutations who were treated with PARP inhibitors.

They found that RAD51 nuclear foci was the only feature common to both the PDXs and the patient samples with primary or acquired resistance to the PARP inhibitors. Samples that were resistant and treated with the PARP inhibitor olaparib showed a higher percentage of RAD51-positive cells than those that were PARP inhibition–sensitive (36% vs 5%; P = .0017). Untreated samples showed a similar result, with 24% of RAD51-positive cells among resistant tumors and 2% among sensitive tumors (P = .0025).

The researchers also showed that resistance to PARP inhibition could be reverted when a PARP inhibitor was combined with an ATM inhibitor. They noted that a phase I trial of olaparib in combination with an ATM inhibitor known as AZD0156 is currently ongoing in patients with solid tumors.

“This emphasizes the need of comprehensive functional tests for measuring HRR activity such as the RAD51 assay to better select patients who will benefit most from PARP inhibitor monotherapy and those who may benefit from a combination therapy,” the authors concluded.