Combination Treatment Strategies to Overcome PARP Inhibitor Resistance

Abstract

Poly(ADP-ribose) polymerase (PARP) enzymes have been shown to be essential for DNA repair pathways, including homologous recombination repair (HRR). Cancers with HRR defects (e.g., BRCA1 and BRCA2 mutations) are targets for PARP inhibitors (PARPis) based on the exploitation of “synthetic lethality”. As a result, PARPis offer a promising treatment option for advanced ovarian and breast cancers with deficiencies in HRR. However, acquired resistance to PARPis has been reported for most tumors, and not all patients with BRCA1/2 mutations respond to PARPis. Therefore, the formulation of effective treatment strategies to overcome resistance to PARPis is urgently necessary. This review summarizes the molecular mechanism of therapeutic action and resistance to PARPis, in addition to emerging combination treatment options involving PARPis.

Keywords

• PARP-1
• PARP inhibitors
• resistance
• combination therapy
• homologous recombination deficiency
• breast cancers