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Acquired Resistance of EGFR-Mutated Lung Cancer to Tyrosine Kinase Inhibitor Treatment Promotes PARP Inhibitor Sensitivity.

Authors
  • Marcar, Lynnette1
  • Bardhan, Kankana1
  • Gheorghiu, Liliana1
  • Dinkelborg, Patrick2
  • Pfäffle, Heike1
  • Liu, Qi1
  • Wang, Meng1
  • Piotrowska, Zofia3
  • Sequist, Lecia V3
  • Borgmann, Kerstin4
  • Settleman, Jeffrey E5
  • Engelman, Jeffrey A5
  • Hata, Aaron N6
  • Willers, Henning7
  • 1 Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • 2 Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Laboratory of Radiobiology and Experimental Radiooncology, University Hospital Eppendorf, Hamburg 20251, Germany. , (Germany)
  • 3 Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • 4 Laboratory of Radiobiology and Experimental Radiooncology, University Hospital Eppendorf, Hamburg 20251, Germany. , (Germany)
  • 5 Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
  • 6 Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • 7 Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: [email protected]
Type
Published Article
Journal
Cell Reports
Publisher
Elsevier
Publication Date
Jun 18, 2019
Volume
27
Issue
12
Identifiers
DOI: 10.1016/j.celrep.2019.05.058
PMID: 31216465
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Lung cancers with oncogenic mutations in the epidermal growth factor receptor (EGFR) invariably acquire resistance to tyrosine kinase inhibitor (TKI) treatment. Vulnerabilities of EGFR TKI-resistant cancer cells that could be therapeutically exploited are incompletely understood. Here, we describe a poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor-sensitive phenotype that is conferred by TKI treatment in vitro and in vivo and appears independent of any particular TKI resistance mechanism. We find that PARP-1 protects cells against cytotoxic reactive oxygen species (ROS) produced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX). Compared to TKI-naive cells, TKI-resistant cells exhibit signs of increased RAC1 activity. PARP-1 catalytic function is required for PARylation of RAC1 at evolutionarily conserved sites in TKI-resistant cells, which restricts NOX-mediated ROS production. Our data identify a role of PARP-1 in controlling ROS levels upon EGFR TKI treatment, with potentially broad implications for therapeutic targeting of the mechanisms that govern the survival of oncogene-driven cancer cells. Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

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