Rapamycin prevents the development and progression of mutant epidermal growth factor receptor lung tumors with the acquired resistance mutation T790M

Cell Rep. 2014 Jun 26;7(6):1824-32. doi: 10.1016/j.celrep.2014.05.039. Epub 2014 Jun 12.

Abstract

Lung cancer in never-smokers is an important disease often characterized by mutations in epidermal growth factor receptor (EGFR), yet risk reduction measures and effective chemopreventive strategies have not been established. We identify mammalian target of rapamycin (mTOR) as potentially valuable target for EGFR mutant lung cancer. mTOR is activated in human lung cancers with EGFR mutations, and this increases with acquisition of T790M mutation. In a mouse model of EGFR mutant lung cancer, mTOR activation is an early event. As a single agent, the mTOR inhibitor rapamycin prevents tumor development, prolongs overall survival, and improves outcomes after treatment with an irreversible EGFR tyrosine kinase inhibitor (TKI). These studies support clinical testing of mTOR inhibitors in order to prevent the development and progression of EGFR mutant lung cancers.

Publication types

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

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / pharmacology*
  • Disease Progression
  • Drug Resistance, Neoplasm
  • ErbB Receptors / genetics*
  • ErbB Receptors / metabolism
  • Humans
  • Lung Neoplasms / enzymology
  • Lung Neoplasms / genetics
  • Lung Neoplasms / prevention & control*
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Random Allocation
  • Sirolimus / pharmacology*
  • TOR Serine-Threonine Kinases / metabolism

Substances

  • Antibiotics, Antineoplastic
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • EGFR protein, human
  • ErbB Receptors
  • Sirolimus