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

Abstract

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.

Exploration of poly (ADP‐ribose) polymerase inhibitor resistance in the treatment of BRCA1/2‐mutated cancer

“…This allows the full-length wild-type protein to be synthesized normally, resulting in genetic reversal of the mutation. 2 Initially, the reversal of protein-truncating mutations in BRCA1/2 was observed in vitro by treating BRCA2-mutated ovarian and pancreatic cancer cell lines with PARPis or cisplatin for an extended period. 71,72 Moreover, Lin et al…”