Reactivation of ERK Signaling Causes Resistance to EGFR Kinase Inhibitors

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

doi:10.1158/2159-8290.cd-12-0103

Abstract

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 erlotinib-resistant 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.

Highlights

Epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are effective clinical therapies for non–small cell lung cancer (NSCLC) patients harboring EGFRmutant cancers
In an effort to overcome the therapeutic limitations of irreversible quinazoline EGFR inhibitors, we previously identified a novel class of irreversible pyrimidine-based EGFR kinase inhibitors [13]
At the time of resistance, we examined the tumors from the treated mice and noted that EGFR phosphorylation was still inhibited by WZ4002, we were able detect the emergence of robust expression of ERK1/2 phosphorylation (Figs. 4D and E and Supplementary Fig. S10)

Summary

Introduction

Epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are effective clinical therapies for non–small cell lung cancer (NSCLC) patients harboring EGFRmutant cancers. Several phase III clinical trials have showed improved clinical efficacy compared with systemic chemotherapy [1,2,3]. Despite these benefits, all patients develop acquired resistance to gefitinib and erlotinib [4]. Irreversible quinazoline-based EGFR inhibitors, including afatinib (BIBW2992) and dacomitinib (PF299804), effectively inhibit the growth of EGFR T790M-containing cell line models in vitro [9, 10]. In clinical studies, afatinib did not prolong survival compared with placebo in patients with NSCLC that had developed acquired resistance to gefitinib or erlotinib [11]. In preclinical studies, resistance of EGFR T790M tumor cells to dacomitinib develops rapidly and is caused by amplification of the T790M-containing allele [12]

Methods

Results

Conclusion