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Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
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Acquired Resistance of EGFR-Mutated Lung Cancer to Tyrosine Kinase Inhibitor Treatment Promotes PARP Inhibitor

Lynnette Marcar1, Kankana Bardhan1, Liliana Gheorghiu1

  • 1Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

Cell Reports
|June 20, 2019
PubMed

Insights

Lung cancer cells resistant to EGFR tyrosine kinase inhibitors (TKIs) become sensitive to PARP-1 inhibitors. This occurs because PARP-1 regulates reactive oxygen species (ROS) production in resistant cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Lung cancers with oncogenic epidermal growth factor receptor (EGFR) mutations often develop resistance to tyrosine kinase inhibitor (TKI) therapy.
  • The vulnerabilities of EGFR TKI-resistant cancer cells remain incompletely understood, limiting therapeutic options.

Purpose of the Study:

  • To identify and characterize vulnerabilities in EGFR TKI-resistant lung cancer cells that can be therapeutically targeted.
  • To investigate the role of poly (ADP-ribose) polymerase 1 (PARP-1) in the survival of TKI-resistant cancer cells.

Main Methods:

  • In vitro and in vivo experiments were conducted to assess the phenotype of TKI-treated lung cancer cells.
  • Investigated the interaction between PARP-1, reactive oxygen species (ROS), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), and RAC1 activity.
  • Assessed the catalytic function of PARP-1 in the PARylation of RAC1 in TKI-resistant cells.

Main Results:

  • EGFR TKI treatment confers a phenotype of sensitivity to poly (ADP-ribose) polymerase 1 (PARP-1) inhibitors, independent of the resistance mechanism.
  • PARP-1 protects cells from cytotoxic reactive oxygen species (ROS) produced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX).
  • TKI-resistant cells show increased RAC1 activity, and PARP-1's catalytic function is required for RAC1 PARylation, which limits NOX-mediated ROS production.

Conclusions:

  • PARP-1 plays a crucial role in managing reactive oxygen species (ROS) levels in lung cancer cells treated with EGFR TKIs.
  • Targeting PARP-1 may offer a therapeutic strategy for overcoming resistance in oncogene-driven cancers.
  • This study reveals a novel mechanism involving PARP-1, RAC1, and ROS in EGFR TKI resistance.
Keywords:
EGFR mutationLung cancerPARP-1RAC1oncogenereactive oxygen speciestyrosine kinase inhibitor

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