Open AccessCrosstalk of DNA double‐strand break repair pathways in poly(ADP‐ribose) polymerase inhibitor treatment of breast cancer susceptibility gene 1/2‐mutated cancer
Author(s) -
Sunada Shigeaki,
Nakanishi Akira,
Miki Yoshio
Publication year - 2018
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13530
Subject(s) - synthetic lethality , poly adp ribose polymerase , dna repair , parp inhibitor , homologous recombination , cancer research , biology , polymerase , dna damage , cancer , cancer cell , genetics , dna
Germline mutations in breast cancer susceptibility gene 1 or 2 ( BRCA 1 or BRCA 2) significantly increase cancer risk in hereditary breast and ovarian cancer syndrome ( HBOC ). Both genes function in the homologous recombination ( HR ) pathway of the DNA double‐strand break ( DSB ) repair process. Therefore, the DNA ‐repair defect characteristic of cancer cells brings about a therapeutic advantage for poly( ADP ‐ribose) polymerase ( PARP ) inhibitor‐induced synthetic lethality. PARP inhibitor‐based therapeutics initially cause cancer lethality but acquired resistance mechanisms have been found and need to be elucidated. In particular, it is essential to understand in detail the mechanism of DNA damage and repair to PARP inhibitor treatment. Further investigations have shown the roles of BRCA 1/2 and its associations to other molecules in the DSB repair system. Notably, the repair pathway chosen in BRCA 1‐deficient cells could be entirely different from that in BRCA 2‐deficient cells after PARP inhibitor treatment. The present review describes synthetic lethality and acquired resistance mechanisms to PARP inhibitor through the DSB repair pathway and subsequent repair process. In addition, recent knowledge of resistance mechanisms is discussed. Our model should contribute to the development of novel therapeutic strategies.