DNA methyltransferase inhibitors induce a BRCAness phenotype that sensitizes NSCLC to PARP inhibitor and ionizing radiation

Rachel Abbotts, Michael J. Topper, Christopher Biondi, Daniel Fontaine, Reena Goswami, Lora Stojanovic, Eun Yong Choi, Lena McLaughlin, Aksinija A. Kogan, Limin Xia, Rena Lapidus, Javed Mahmood, Stephen B. Baylin, Feyruz V. Rassool

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)22609-22618
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number45
DOIs
StatePublished - Nov 5 2019

Keywords

  • DNA repair
  • Homologous recombination defect
  • Lung cancer
  • Nonhomologous end-joining
  • Poly (ADP-ribose) polymerase inhibitors

ASJC Scopus subject areas

  • General

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  • Cite this

    Abbotts, R., Topper, M. J., Biondi, C., Fontaine, D., Goswami, R., Stojanovic, L., Choi, E. Y., McLaughlin, L., Kogan, A. A., Xia, L., Lapidus, R., Mahmood, J., Baylin, S. B., & Rassool, F. V. (2019). DNA methyltransferase inhibitors induce a BRCAness phenotype that sensitizes NSCLC to PARP inhibitor and ionizing radiation. Proceedings of the National Academy of Sciences of the United States of America, 116(45), 22609-22618. https://doi.org/10.1073/pnas.1903765116