Molecular phenotype predicts sensitivity of squamous cell carcinoma of the head and neck to epidermal growth factor receptor inhibition

Natalie R. Young, Jing Liu, Carolyn Pierce, Tai Fen Wei, Tatyana Grushko, Olufunmilayo I. Olopade, Wanqing Liu, Christine Shen, Tanguy Y. Seiwert, Ezra E.W. Cohen

Research output: Contribution to journalArticle

Abstract

Despite nearly universal expression of the wild-type epidermal growth factor receptor (EGFR) and reproducible activity of EGFR inhibitors in patients with squamous cell carcinoma of the head and neck (SCCHN), the majority of patients will not have objective responses. The mechanisms of this intrinsic resistance are not well established. We hypothesized that sensitivity to EGFR inhibitors can be predicted based on the inhibitors' effects on downstream signaling. Cell viability assays were used to assess sensitivity to the EGFR inhibitor gefitinib (ZD1839) in 8 SCCHN cell lines. Fluorescence in-situ hybridization showed the two most sensitive lines to be highly gene-amplified for EGFR. Western blotting confirmed that phosphoEGFR was inhibited at low concentrations of gefitinib in all lines tested. Phosphorylation of downstream signaling protein AKT was inhibited in sensitive lines while inhibition of phosphoERK displayed no relationship to gefitinib efficacy. Phosphatase and tensin homolog (PTEN) expression was evident in all cell lines. Activating PIK3CA mutations were found in two resistant cell lines where pAKT was not inhibited by gefitinib. In resistant cell lines harboring PIK3CA mutations, a PI3K inhibitor, LY294002, or AKT siRNA reduced cell viability with an additive effect demonstrated in combination with gefitinib. Additionally, LY294002 alone and in combination with gefitinib, was effective at treating PIK3CA mutated tumors xenografted into nude mice. Taken together this suggests that constitutively active AKT is a mechanism of intrinsic gefitinib resistance in SCCHN. This resistance can be overcome through targeting of the PI3K/AKT pathway in combination with EGFR inhibition.

Original languageEnglish (US)
Pages (from-to)359-368
Number of pages10
JournalMolecular oncology
Volume7
Issue number3
DOIs
StatePublished - Jun 2013
Externally publishedYes

Keywords

  • AKT
  • EGFR
  • Gefitinib
  • Head and neck squamous cell carcinoma
  • PIK3CA mutations

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Oncology
  • Cancer Research

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