Differential sensitivity of glioma- versus lung cancer-specific EGFR mutations to EGFR kinase inhibitors

Igor Vivanco, H. Ian Robins, Daniel Rohle, Carl Campos, Christian Grommes, Phioanh Leia Nghiemphu, Sara Kubek, Barbara Oldrini, Milan G. Chheda, Nicolas Yannuzzi, Hui Tao, Shaojun Zhu, Akio Iwanami, Daisuke Kuga, Julie Dang, Alicia Pedraza, Cameron W. Brennan, Adriana Heguy, Linda M. Liau, Frank LiebermanW. K. Alfred Yung, Mark R. Gilbert, David A. Reardon, Jan Drappatz, Patrick Y. Wen, Kathleen R. Lamborn, Susan M. Chang, Michael D. Prados, Howard A. Fine, Steve Horvath, Nian Wu, Andrew B. Lassman, Lisa M. DeAngelis, William H. Yong, John G. Kuhn, Paul S. Mischel, Minesh P. Mehta, Timothy F. Cloughesy, Ingo K. Mellinghoff

Research output: Contribution to journalArticlepeer-review

199 Citations (Scopus)

Abstract

Activation of the epidermal growth factor receptor (EGFR) in glioblastoma (GBM) occurs through mutations or deletions in the extracellular (EC) domain. Unlike lung cancers with EGFR kinase domain (KD) mutations, GBMs respond poorly to the EGFR inhibitor erlotinib. Using RNAi, we show that GBM cells carrying EGFR EC mutations display EGFR addiction. In contrast to KD mutants found in lung cancer, glioma-specific EGFR EC mutants are poorly inhibited by EGFR inhibitors that target the active kinase conformation (e.g., erlotinib). Inhibitors that bind to the inactive EGFR conformation, however, potently inhibit EGFR EC mutants and induce cell death in EGFR-mutant GBM cells. Our results provide first evidence for single kinase addiction in GBM and suggest that the disappointing clinical activity of first-generation EGFR inhibitors in GBM versus lung cancer may be attributed to the different conformational requirements of mutant EGFR in these 2 cancer types. Significance: Approximately 40% of human glioblastomas harbor oncogenic EGFR alterations, but attempts to therapeutically target EGFR with first-generation EGFR kinase inhibitors have failed. Here, we demonstrate selective sensitivity of glioma-specific EGFR mutants to ATP-site competitive EGFR kinase inhibitors that target the inactive conformation of the catalytic domain.

Original languageEnglish
Pages (from-to)458-471
Number of pages14
JournalCancer Discovery
Volume2
Issue number5
DOIs
Publication statusPublished - 2012 May

ASJC Scopus subject areas

  • Oncology

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