Aberrations in DNA repair pathways in cancer and therapeutic significances

Cancer cells show various types of mutations and aberrant expression in genes involved in DNA repair responses. These alterations induce genome instability and promote carcinogenesis steps and cancer progression processes. These defects in DNA repair have also been considered as suitable targets for...

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Bibliographic Details
Published in:Seminars in cancer biology 2019-10, Vol.58, p.29-46
Main Authors: Motegi, Akira, Masutani, Mitsuko, Yoshioka, Ken-ichi, Bessho, Tadayoshi
Format: Article
Language:English
Subjects:
Animals
Carcinogenesis - genetics
DNA Repair - genetics
Genomic Instability - genetics
Homologous recombination repair
Humans
Mismatch repair
Mutation - genetics
Neoplasms - genetics
Nucleotide excision repair
PARP
Synthetic lethality
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Summary:Cancer cells show various types of mutations and aberrant expression in genes involved in DNA repair responses. These alterations induce genome instability and promote carcinogenesis steps and cancer progression processes. These defects in DNA repair have also been considered as suitable targets for cancer therapies. A most effective target so far clinically demonstrated is “homologous recombination repair defect”, such as BRCA1/2 mutations, shown to cause synthetic lethality with inhibitors of poly(ADP-ribose) polymerase (PARP), which in turn is involved in DNA repair as well as multiple physiological processes. Different approaches targeting genomic instability, including immune therapy targeting mismatch-repair deficiency, have also recently been demonstrated to be promising strategies. In these DNA repair targeting-strategies, common issues could be how to optimize treatment and suppress/conquer the development of drug resistance. In this article, we review the extending framework of DNA repair response pathways and the potential impact of exploiting those defects on cancer treatments, including chemotherapy, radiation therapy and immune therapy.
ISSN:1044-579X
1096-3650
DOI:10.1016/j.semcancer.2019.02.005