期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 45, 页码 22609-22618出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1903765116
关键词
DNA repair; lung cancer; homologous recombination defect; nonhomologous end-joining; poly (ADP-ribose) polymerase inhibitors
资金
- National Cancer Institute (NCI) University of Maryland Cancer Canter Support Grant [P30CA134274]
- NCI [R25CA186872]
- Adelson Medical Research Foundation
- Maryland Cigarette Restitution funds
- Van Andel Research Institute-Stand Up 2 Cancer
A minority of cancers have breast cancer gene (BRCA) mutations that confer sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis), but the role for PARPis in BRCA-proficient cancers is not well established. This suggests the need for novel combination therapies to expand the use of these drugs. Recent reports that low doses of DNA methyltransferase inhibitors (DNMTis) plus PARPis enhance PARPi efficacy in BRCA-proficient AML subtypes, breast, and ovarian cancer open up the possibility that this strategy may apply to other sporadic cancers. We identify a key mechanistic aspect of this combination therapy in nonsmall cell lung cancer (NSCLC): that the DNMTi component creates a BRCAness phenotype through downregulating expression of key homologous recombination and nonhomologous end-joining (NHEJ) genes. Importantly, from a translational perspective, the above changes in DNA repair processes allow our combinatorial PARPi and DNMTi therapy to robustly sensitize NSCLC cells to ionizing radiation in vitro and in vivo. Our combinatorial approach introduces a biomarker strategy and a potential therapy paradigm for treating BRCA-proficient cancers like NSCLC.
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