Resistance to parp inhibitors mediated by secondary brca1/2 mutations

Abstract

PARP inhibitors are a promising class of chemotherapy agents that have shown efficacy in the treatment of BRCA1/2-deficient tumors. Treatment with these small molecule inhibitors in a homologous recombination repair (HRR) deficient background results in synthetic lethality. However, cancer cells can become resistant to PARP inhibitors by several different mechanisms. A major mechanism of PARP inhibitor resistance is restoration of functional BRCA1/2 by secondary BRCA1/2 mutation. BRCA1/2 restoration cancels synthetic lethality as it leads to functional HRR-mediated DNA repair. Loss of 53BP1 expression in BRCA1- mutated cancer cells can also lead to PARP inhibitor resistance by partial restoration of HRR. Additional mechanisms of PARP inhibitor resistance include increased P-glycoprotein expression that results in increased efflux of the drug and loss of PARP1 expression that prevents formation of toxic DNA-PARP1 lesions. Here, we focus on PARP inhibitor resistance by BRCA1/2 restoration and potential clinical implications of this phenomenon. We also briefly discuss the other known and possible mechanisms of PARP resistance.