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PARP inhibitors in breast cancer: Bringing synthetic lethality to the bedside
Author(s) -
Turk Anita A.,
Wisinski Kari B.
Publication year - 2018
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.31307
Subject(s) - synthetic lethality , olaparib , breast cancer , medicine , parp inhibitor , ovarian cancer , cancer research , cancer , brca mutation , poly adp ribose polymerase , dna repair , oncology , polymerase , biology , genetics , dna
Individuals with breast and ovarian cancer susceptibility gene 1 ( BRCA1 ) or BRCA2 germline mutations have a significantly increased lifetime risk for breast and ovarian cancers. BRCA ‐mutant cancer cells have abnormal homologous recombination (HR) repair of DNA. In these tumors, the base excision repair (BER) pathway is important for cell survival. The poly(adenosine diphosphate‐ribose) polymerase (PARP) enzymes play a key role in BER, and PARP inhibitors are effective in causing cell death in BRCA ‐mutant cells while sparing normal cells—a concept called synthetic lethality . PARP inhibitors are the first cancer therapeutics designed to exploit synthetic lethality. Recent clinical trials in BRCA ‐mutant, metastatic breast cancer demonstrated improved outcomes with single‐agent PARP inhibitors (olaparib and talazoparib) over chemotherapy. However, resistance to PARP inhibitors remains a challenge. Primarily due to myelosuppression, the combination of PARP inhibitors with chemotherapy has been difficult. Novel combinations with chemotherapy, immunotherapy, and other targeted therapies are being pursued. In this review, the authors discuss current knowledge of PARP inhibitors in BRCA ‐mutant breast cancer and potential future directions for these agents. Cancer 2018;124:2498‐506 . © 2018 American Cancer Society .