Molecular targeted drugs resistance impairs double-strand break repair and sensitizes ER-positive breast cancer to PARP inhibitors.

Background: There are various treatments for estrogen-positive breast cancer, mainly hormone therapy and molecular-targeted drugs. Acquiring resistance to these drugs is a major clinical problem. Additionally, little is known about the effect of drug resistance on the DNA repair mechanism. Poly ADP ribose polymerase (PARP) inhibitors currently used for treating HER2-negative metastatic breast cancer with BRCA mutations have been shown to be effective in BRCA-deficient cells with impaired homologous recombination repair. Here, we investigated the effect of drug resistance acquisition on the DNA repair mechanism and the effect of PARP inhibitors on ER (estrogen receptor) -positive breast cancer.

Methods: We investigated changes in the expression of DNA repair mechanism-related factors and repair ability of double-strand breaks (DSB) in various drug-resistant cell lines established in our laboratory. Additionally, PARP inhibitor susceptibility was investigated using olaparib.

Results: DSB repairs in MCF-7 and hormone therapy-resistant model cells were normal, and these cells demonstrated low sensitivity to olaparib. The resistant cell lines against CDK4/6 inhibitors, fulvestrant and mTOR/PI3K inhibitors showed decreased DSB repair ability and high olaparib sensitivity. They showed low sensitivity to CDK4/6 inhibitors, a close link between acquiring resistance to CDK4/6 inhibitors and hypersensitivity to olaparib.

Conclusions: Our study suggests some cases of acquiring drug resistance impairs DSB repair ability and sensitizes ER-positive breast cancer to PARP inhibitors.