Acquired Resistance of EGFR-Mutated Lung Cancer to Tyrosine Kinase Inhibitor Treatment Promotes PARP Inhibitor Sensitivity
Lynnette Marcar,
Kankana Bardhan,
Liliana Gheorghiu,
Patrick Dinkelborg,
Heike Pfäffle,
Qi Liu,
Meng Wang,
Zofia Piotrowska,
Lecia V. Sequist,
Kerstin Borgmann,
Jeffrey E. Settleman,
Jeffrey A. Engelman,
Aaron N. Hata,
Henning Willers
Affiliations
Lynnette Marcar
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Kankana Bardhan
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Liliana Gheorghiu
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Patrick Dinkelborg
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
Heike Pfäffle
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Qi Liu
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Meng Wang
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Zofia Piotrowska
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Lecia V. Sequist
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
Kerstin Borgmann
Laboratory of Radiobiology and Experimental Radiooncology, University Hospital Eppendorf, Hamburg 20251, Germany
Jeffrey E. Settleman
Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
Jeffrey A. Engelman
Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA
Aaron N. Hata
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
Henning Willers
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Corresponding author
Summary: 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. : Marcar et al. show that epidermal growth factor receptor mutant (EGFRmut) lung cancer cells with acquired resistance to tyrosine kinase inhibitors (TKIs) exhibit PARP-1 dependence for survival. PARP-1 catalytic function is required for PARylation of RAC1, which restricts NOX-mediated production of cytotoxic reactive oxygen species. Findings suggest combining TKI with PARP inhibition in EGFRmut cancers. Keywords: Lung cancer, oncogene, EGFR mutation, tyrosine kinase inhibitor, PARP-1, reactive oxygen species, RAC1
