Approaching Resistance to Targeted Inhibition of PI3K in Breast Cancer

Abstract

The phosphatidylinositol 3- kinase (PI3K)-pathway is frequently activated in breast cancer; therefore, considerable effort is focused on identifying compounds that can inhibit specific pathway components, in particular the hallmark oncogene PIK3CA. While 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/mTOR-inhibitor NVP-BEZ235 and by genome-wide copy-number analyses identified MYC and eIF4E amplification within the resistant cells. Importantly, either MYC or eIF4E were 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.

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Document Details

Document Type
Technical Report
Publication Date
Oct 01, 2011
Accession Number
ADA555900

Entities

People

  • Nina Ilic

Organizations

  • Harvard Medical School

Tags

DTIC Thesaurus Topics

  • Breast Cancer
  • Cell Line
  • Cell Physiological Processes
  • Cells
  • Chemical Synthesis
  • Chemistry
  • Crystal Structure
  • Fibroblasts
  • Genetics
  • Health Services
  • Peptide Growth Factors
  • Proteins

Fields of Study

  • Biology

Readers

  • Molecular Biology and Genetics
  • Molecular and genetic basis of cancer.
  • Systems Analysis and Design

Technology Areas

  • Biotechnology