Crosstalk of DNA double‐strand break repair pathways in poly(ADP‐ribose) polymerase inhibitor treatment of breast cancer susceptibility gene 1/2‐mutated cancer. Issue 4 (6th March 2018)

• Record Type: Journal Article
• Authors: Sunada, Shigeaki; Nakanishi, Akira; Miki, Yoshio
• Is Part Of: Cancer science. Volume 109:Issue 4(2018)
• Page Start: 893
• Page End: 899
• Publication Date: 2018-03-06
• Subjects: DNA replication -- HBOC syndrome -- homologous recombination -- non‐homologous DNA end‐joining -- PARP inhibitor; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.13530
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract : Germline mutations in breast cancer susceptibility gene 1 or 2 (BRCA1 or BRCA2) 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 BRCA1/2 and its associations to other molecules in the DSB repair system. Notably, the repair pathway chosen in BRCA1‐deficient cells could be entirely different from that in BRCA2‐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. Abstract : Poly(ADP‐ribose) polymerase (PARP) inhibitor induces single‐ended double‐strand break (seDSB) during DNA replication in S‐phase. seDSB is repaired by two major pathways: homologous recombination (HR) or non‐homologous end joining (NHEJ) as a result of DSB repair pathway choice mechanism in S/G2 phase. We explain PARP inhibitor‐induced synthetic lethality and acquired resistance mechanism in BRCA1/2‐mutated cancer cells through the repair choice model.