RAS-MAPK Dependence Underlies a Rational Polytherapy Strategy in EML4-ALK-positive Lung Cancer

Nat Med. 2015 Sep;21(9):1038-47. doi: 10.1038/nm.3930. Epub 2015 Aug 24.

Abstract

One strategy for combating cancer-drug resistance is to deploy rational polytherapy up front that suppresses the survival and emergence of resistant tumor cells. Here we demonstrate in models of lung adenocarcinoma harboring the oncogenic fusion of ALK and EML4 that the GTPase RAS-mitogen-activated protein kinase (MAPK) pathway, but not other known ALK effectors, is required for tumor-cell survival. EML4-ALK activated RAS-MAPK signaling by engaging all three major RAS isoforms through the HELP domain of EML4. Reactivation of the MAPK pathway via either a gain in the number of copies of the gene encoding wild-type K-RAS (KRAS(WT)) or decreased expression of the MAPK phosphatase DUSP6 promoted resistance to ALK inhibitors in vitro, and each was associated with resistance to ALK inhibitors in individuals with EML4-ALK-positive lung adenocarcinoma. Upfront inhibition of both ALK and the kinase MEK enhanced both the magnitude and duration of the initial response in preclinical models of EML4-ALK lung adenocarcinoma. Our findings identify RAS-MAPK dependence as a hallmark of EML4-ALK lung adenocarcinoma and provide a rationale for the upfront inhibition of both ALK and MEK to forestall resistance and improve patient outcomes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Dual Specificity Phosphatase 6 / physiology
  • Humans
  • Lung Neoplasms / drug therapy*
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / physiology*
  • Oncogene Proteins, Fusion / analysis
  • Oncogene Proteins, Fusion / physiology*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins p21(ras)
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • ras Proteins / genetics
  • ras Proteins / physiology*

Substances

  • EML4-ALK fusion protein, human
  • KRAS protein, human
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases
  • Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • DUSP6 protein, human
  • Dual Specificity Phosphatase 6
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins