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.; Janne, 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 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.
Journal Title: Cancer discovery
Volume: 2
Issue: 10
ISSN: 2159-8290; 2159-8274
Publisher: Unknown  
Journal Place: United States
Date Published: 2012
Start Page: 934
End Page: 947
Language: eng
Notes: LR: 20141120; GR: K08 CA127350/CA/NCI NIH HHS/United States; GR: K08CA127350/CA/NCI NIH HHS/United States; GR: P01CA154303/CA/NCI NIH HHS/United States; GR: P50 CA090578/CA/NCI NIH HHS/United States; GR: P50CA090578/CA/NCI NIH HHS/United States; GR: R01 CA114465/CA/NCI NIH HHS/United States; GR: R01 CA135257/CA/NCI NIH HHS/United States; GR: R01CA114465/CA/NCI NIH HHS/United States; GR: R01CA135257/CA/NCI NIH HHS/United States; JID: 101561693; 0 (Acrylamides); 0 (Antineoplastic Agents); 0 (Protein Kinase Inhibitors); 0 (Pyrimidines); 0 (Quinazolines); 0 (WZ4002); EC (EGFR protein, human); EC (ERBB2 protein, human); EC (Receptor, Epidermal Growth Factor); EC (Receptor, ErbB-2); EC (Mitogen-Activated Protein Kinase 1); J4T82NDH7E (erlotinib); S65743JHBS (gefitinib); NIHMS410882; OID: NLM: NIHMS410882; OID: NLM: PMC3477553; 2012/09/07 [aheadofprint]; 2012/09/27 [aheadofprint]; ppublish