Reactivation of ERK signaling causes resistance to EGFR Kinase inhibitors

Dalia Ercan, Chunxiao Xu, Masahiko Yanagita, Calixte S. Monast, Christine A. Pratilas, Joan Montero, Mohit Butaney, Takeshi Shimamura, Lynette Sholl, Elena V. Ivanova, Madhavi Tadi, Andrew Rogers, Claire Repellin, Marzia Capelletti, Ophélia Maertens, Eva M. Goetz, Anthony Letai, Levi A. Garraway, Matthew J. Lazzara, Neal RosenNathanael S. Gray, Kwok Kin Wong, Pasi A. Jänne

Research output: Contribution to journalArticlepeer-review


The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here, we show, in multiple complementary models, that resistance to WZ4002 develops through aberrant activation of extracellular signal-regulated kinase (ERK) signaling caused by either an amplification of mitogen-activated protein kinase 1 (MAPK1) or by downregulation of negative regulators of ERK signaling. Inhibition of MAP-ERK kinase (MEK) or ERK restores sensitivity to WZ4002 and prevents the emergence of drug resistance. We further identify MAPK1 amplification in an erlotinibresistant EGFR -mutant non-small cell lung carcinoma patient. In addition, the WZ4002-resistant MAPK1 -amplified cells also show an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy. Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rational combination therapies that should be evaluated in clinical trials.

Original languageEnglish (US)
Pages (from-to)934-947
Number of pages14
JournalCancer discovery
Issue number10
StatePublished - Oct 2012
Externally publishedYes

ASJC Scopus subject areas

  • Oncology


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