Aberrant epidermal growth factor receptor signaling and enhanced sensitivity to EGFR inhibitors in lung cancer

Joseph Amann, Shailaja Kalyankrishna, Pierre P. Massion, Joyce E. Ohm, Luc Girard, Hisayuki Shigematsu, Michael Peyton, Denise Juroske, Yuhui Huang, J. Stuart Salmon, Young H. Kim, Jonathan R. Pollack, Kiyoshi Yanagisawa, Adi Gazdar, John D. Minna, Jonathan M. Kurie, David P. Carbone

Research output: Contribution to journalArticle

361 Scopus citations

Abstract

Epidermal growth factor receptor (EGFR) is occasionally amplified and/or mutated in non-small cell lung cancer (NSCLC) and can be coexpressed with other members of the HER receptor family to form functional heterodimers. We therefore investigated lung cancer cell lines for alterations in EGFR gene copy number, enhanced expression of EGFR and other HER family members, and EGFR coding sequence mutations and correlated these findings with response to treatment with the EGFR inhibitors and the kinetics of ligand-induced signaling. We show here that somatic deletions in the tyrosine kinase domain of EGFR were associated with increased EGFR gene copy number in NSCLC. Treatment with the specific EGFR tyrosine kinase inhibitors (TKI) gefitinib or erlotinib or the EGFR inhibitory antibody cetuximab induced apoptosis of HCC827, a NSCLC cell line with EGFR gene amplification and an exon 19 deletion. H1819, a NSCLC cell line that expresses high levels of EGFR, ErbB2, and ErbB3 but has wild-type EGFR, showed intermediate sensitivity to TKIs. In both cell lines, ligand-induced receptor tyrosine phosphorylation was delayed and prolonged and AKT was constitutively phosphorylated (but remained inhibitable by EGFR TKI). Thus, in addition to EGFR mutations, other factors in NSCLC cells, such as high expression of ErbB family members, may constitutively activate AKT and sensitize cells to EGFR inhibitors.

Original languageEnglish (US)
Pages (from-to)226-235
Number of pages10
JournalCancer research
Volume65
Issue number1
StatePublished - Jan 1 2005

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Amann, J., Kalyankrishna, S., Massion, P. P., Ohm, J. E., Girard, L., Shigematsu, H., Peyton, M., Juroske, D., Huang, Y., Salmon, J. S., Kim, Y. H., Pollack, J. R., Yanagisawa, K., Gazdar, A., Minna, J. D., Kurie, J. M., & Carbone, D. P. (2005). Aberrant epidermal growth factor receptor signaling and enhanced sensitivity to EGFR inhibitors in lung cancer. Cancer research, 65(1), 226-235.