TY - JOUR
T1 - Mechanisms of PARP1 inhibitor resistance and their implications for cancer treatment
AU - Jackson, Lindsey M.
AU - Moldovan, George Lucian
N1 - Funding Information:
National Institutes of Health [R01ES026184 and R01GM134681 to G.-L.M.; F31CA275340 to L.M.J.]. Conflict of interest statement. None declared.
Publisher Copyright:
© The Author(s) 2022.
PY - 2022/12/1
Y1 - 2022/12/1
N2 - The discovery of synthetic lethality as a result of the combined loss of PARP1 and BRCA has revolutionized the treatment of DNA repair-deficient cancers. With the development of PARP inhibitors, patients displaying germline or somatic mutations in BRCA1 or BRCA2 were presented with a novel therapeutic strategy. However, a large subset of patients do not respond to PARP inhibitors. Furthermore, many of those who do respond eventually acquire resistance. As such, combating de novo and acquired resistance to PARP inhibitors remains an obstacle in achieving durable responses in patients. In this review, we touch on some of the key mechanisms of PARP inhibitor resistance, including restoration of homologous recombination, replication fork stabilization and suppression of single-stranded DNA gap accumulation, as well as address novel approaches for overcoming PARP inhibitor resistance.
AB - The discovery of synthetic lethality as a result of the combined loss of PARP1 and BRCA has revolutionized the treatment of DNA repair-deficient cancers. With the development of PARP inhibitors, patients displaying germline or somatic mutations in BRCA1 or BRCA2 were presented with a novel therapeutic strategy. However, a large subset of patients do not respond to PARP inhibitors. Furthermore, many of those who do respond eventually acquire resistance. As such, combating de novo and acquired resistance to PARP inhibitors remains an obstacle in achieving durable responses in patients. In this review, we touch on some of the key mechanisms of PARP inhibitor resistance, including restoration of homologous recombination, replication fork stabilization and suppression of single-stranded DNA gap accumulation, as well as address novel approaches for overcoming PARP inhibitor resistance.
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U2 - 10.1093/narcan/zcac042
DO - 10.1093/narcan/zcac042
M3 - Article
C2 - 36568963
AN - SCOPUS:85149885893
SN - 2632-8674
VL - 4
JO - NAR Cancer
JF - NAR Cancer
IS - 4
M1 - zcac042
ER -
