Mechanisms of PARP-Inhibitor-Resistance in BRCA-Mutated Breast Cancer and New Therapeutic Approaches

Simple Summary Poly (ADP-ribose) polymerase (PARP) inhibitors treat breast and ovarian cancers. PARP-inhibition (PARPi), which affects cell survival by re-regulating DNA repair mechanisms, is known as one of the promising methods in terms of treatment protocols. However, resistance to PARP inhibitors causes disruptions to this treatment method. This study discusses the mechanisms that cause PARP-inhibitor-resistance and the possible therapeutic strategies to overcome them. The recent success of Poly (ADP-ribose) polymerase (PARP) inhibitors has led to the approval of four different PARP inhibitors for the treatment of BRCA1/2-mutant breast and ovarian cancers. About 40-50% of BRCA1/2-mutated patients do not respond to PARP inhibitors due to a preexisting innate or intrinsic resistance; the majority of patients who initially respond to the therapy inevitably develop acquired resistance. However, subsets of patients experience a long-term response (>2 years) to treatment with PARP inhibitors. Poly (ADP-ribose) polymerase 1 (PARP1) is an enzyme that plays an important role in the recognition and repair of DNA damage. PARP inhibitors induce "synthetic lethality" in patients with tumors with a homologous-recombination-deficiency (HRD). Several molecular mechanisms have been identified as causing PARP-inhibitor-resistance. In this review, we focus on the molecular mechanisms underlying the PARP-inhibitor-resistance in BRCA-mutated breast cancer and summarize potential therapeutic strategies to overcome the resistance mechanisms.