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.
authors.affiliation: Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Dalia
authors.initials: D
authors.lastname: Ercan
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Xu
authors.forename: Masahiko
authors.initials: M
authors.lastname: Yanagita
authors.forename: Calixte S
authors.initials: CS
authors.lastname: Monast
authors.forename: Christine A
authors.initials: CA
authors.lastname: Pratilas
authors.forename: Joan
authors.initials: J
authors.lastname: Montero
authors.forename: Mohit
authors.initials: M
authors.lastname: Butaney
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shimamura
authors.forename: Lynette
authors.initials: L
authors.lastname: Sholl
authors.forename: Elena V
authors.initials: EV
authors.lastname: Ivanova
authors.forename: Madhavi
authors.initials: M
authors.lastname: Tadi
authors.forename: Andrew
authors.initials: A
authors.lastname: Rogers
authors.forename: Claire
authors.initials: C
authors.lastname: Repellin
authors.forename: Marzia
authors.initials: M
authors.lastname: Capelletti
authors.forename: Ophélia
authors.initials: O
authors.lastname: Maertens
authors.forename: Eva M
authors.initials: EM
authors.lastname: Goetz
authors.forename: Anthony
authors.initials: A
authors.lastname: Letai
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Lazzara
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
mesh_terms: D000178:Acrylamides / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D019950:Mitogen-Activated Protein Kinase 1; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C571455:WZ4002; C512478:EGFR protein, human; C508053:ERBB2 protein, human