Focal adhesion kinase inhibitor defactinib enhances olaparib-induced suppression of BRCA-proficient breast cancer cell proliferation.

Poly ADP-ribose polymerase (PARP) inhibitors exhibit high activity for carcinomas with homologous recombination (HR) deficiency, such as BRCA1/2 mutations. PARP inhibitors are primarily administered to patients with breast cancer with BRCA germline mutations; therefore, the use of these inhibitors for breast cancer has been limited. The present study was undertaken with the aim of proposing a new treatment for BRCA-proficient breast cancer. This study investigated drugs with good safety profiles to enhance the growth inhibitory effects of the most commonly used PARP inhibitor, olaparib, in BRCA-proficient MDA-MB-231 cells. The focal adhesion kinase (FAK) inhibitor defactinib, which suppressed BRCA expression at the mRNA level, was identified as a candidate by screening for BRCA down-regulators. Defactinib also enhanced olaparib-induced inhibition in other BRCA-proficient breast cancer cell proliferation. Furthermore, apoptosis was more strongly induced by the combination of olaparib and defactinib than by either agent alone. To elucidate the molecular mechanisms underlying the enhanced induction of apoptosis, a Western blot analysis of apoptosis-related proteins indicated the contribution of the downregulated expression of X-linked inhibitor of apoptosis protein. This indicates the efficiency of the combination treatment of the PARP inhibitor olaparib and the FAK inhibitor defactinib for breast cancer cells, which may be useful for BRCA-proficient breast cancer or carcinomas that acquire resistance to PARP inhibitors.