Reactivation of ERK signaling causes resistance to EGFR Kinase inhibitors Journal Article


Authors: Ercan, D.; Xu, C.; Yanagita, M.; Monast, C. S.; Pratilas, C. A.; Montero, J.; Butaney, M.; Shimamura, T.; Sholl, L.; Ivanova, E. V.; Tadi, M.; Rogers, A.; Repellin, C.; Capelletti, M.; Maertens, O.; Goetz, E. M.; Letai, A.; Garraway, L. A.; Lazzara, M. J.; Rosen, N.; Gray, N. S.; Wong, K. K.; Jänne, P. A.
Article Title: Reactivation of ERK signaling causes resistance to EGFR Kinase inhibitors
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 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. ©2012 AACR.
Keywords: immunohistochemistry; signal transduction; mitogen activated protein kinase; clinical article; controlled study; human tissue; protein expression; unclassified drug; human cell; single nucleotide polymorphism; mutation; erlotinib; nonhuman; antineoplastic agents; paclitaxel; nuclear magnetic resonance imaging; cell proliferation; mouse; animals; mice; animal tissue; cell viability; gene amplification; map kinase signaling system; tumor volume; etoposide; lung non small cell cancer; carcinoma, non-small-cell lung; lung neoplasms; epidermal growth factor receptor; animal experiment; animal model; bim protein; receptor, epidermal growth factor; drug resistance, neoplasm; cell line, tumor; pyrimidines; mutational analysis; protein kinase inhibitors; fluorescence in situ hybridization; nucleotide sequence; western blotting; mitogen activated protein kinase 1; mitogen activated protein kinase 3; down regulation; receptor, erbb-2; real time polymerase chain reaction; gene dosage; tumor growth; quinazolines; drug sensitivity; fluorescence activated cell sorting; mitogen activated protein kinase kinase; internalization; epidermal growth factor receptor kinase inhibitor; 2 (2 chloro 4 iodoanilino) n cyclopropylmethoxy 3,4 difluorobenzamide; mitogen-activated protein kinase 1; molecular targeted therapy; bh3 protein; staurosporine; acrylamides; trametinib; dual specificity phosphatase 6; 2 (2 chloro 4 iodoanilino) n cyclopropylmethoxy 3, 4 difluorobenzamide; 8 [4 (1 aminocyclobutyl) phenyl] 9 phenyl 1, 2, 4 triazolo [3, 4 f] [1, 6] naphthyridin 3 (2h) one; 8 [4 (1 aminocyclobutyl)phenyl] 9 phenyl 1,2,4 triazolo[3,4 f][1,6]naphthyridin 3(2h) one; wz4002; enzyme reactivation; protien phosphorylation
Journal Title: Cancer Discovery
Volume: 2
Issue: 10
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2012-10-01
Start Page: 934
End Page: 947
Language: English
DOI: 10.1158/2159-8290.cd-12-0103
PROVIDER: scopus
PMCID: PMC3477553
PUBMED: 22961667
DOI/URL:
Notes: --- - "Cited By (since 1996): 1" - "Export Date: 3 December 2012" - "Molecular Sequence Numbers: GENBANK: GSE37700;" - "Source: Scopus"
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MSK Authors
  1. Neal Rosen
    359 Rosen
  2. Madhavi Tadi
    11 Tadi