PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E (eIF4E) axis

Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):E699-708. doi: 10.1073/pnas.1108237108. Epub 2011 Aug 29.

Abstract

The PI3K pathway is frequently activated in cancer; therefore, considerable effort is focused on identifying compounds that can inhibit specific pathway components, particularly the hallmark oncogene PIK3CA. Although targeted inhibition of a cancer survival gene holds significant promise, there are concerns that drug resistance may emerge within the cancerous cells, thus limiting clinical efficacy. Using genetically defined human mammary epithelial cells, we evolved resistance to the PI3K/mammalian target of rapamycin (mTOR) inhibitor BEZ235, and by genome-wide copy number analyses, we identified MYC and eIF4E amplification within the resistant cells. Importantly, either MYC or eukaryotic translation initiation factor 4E (eIF4E) was required to bypass pharmacological PI3K/mTOR inhibition in resistant cells. Furthermore, these cells displayed elevated 5' cap-dependent protein translation. Collectively, these findings suggest that analysis of drivers of protein translation could facilitate the identification of cancer lesions that confer resistance to PI3K pathway-targeted drugs.

Publication types

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

MeSH terms

  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / drug effects
  • Eukaryotic Initiation Factor-4E / genetics*
  • Eukaryotic Initiation Factor-4E / metabolism
  • Female
  • Gene Amplification* / drug effects
  • Gene Dosage / genetics
  • Genome, Human / genetics
  • Humans
  • Imidazoles / pharmacology
  • Molecular Targeted Therapy*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Point Mutation / genetics
  • Protein Biosynthesis / drug effects
  • Proto-Oncogene Proteins c-myc / genetics*
  • Proto-Oncogene Proteins c-myc / metabolism
  • Quinolines / pharmacology
  • RNA Caps / metabolism
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / metabolism
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism
  • Up-Regulation / drug effects

Substances

  • CRTC1 protein, human
  • CRTC2 protein, human
  • Eukaryotic Initiation Factor-4E
  • Imidazoles
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-myc
  • Quinolines
  • RNA Caps
  • Transcription Factors
  • TOR Serine-Threonine Kinases
  • dactolisib

Associated data

  • GEO/GSE25173