title: ERK mutations confer resistance to mitogen-activated protein kinase pathway inhibitors.
abstract: The use of targeted therapeutics directed against BRAF(V600)-mutant metastatic melanoma improves progression-free survival in many patients; however, acquired drug resistance remains a major medical challenge. By far, the most common clinical resistance mechanism involves reactivation of the MAPK (RAF/MEK/ERK) pathway by a variety of mechanisms. Thus, targeting ERK itself has emerged as an attractive therapeutic concept, and several ERK inhibitors have entered clinical trials. We sought to preemptively determine mutations in ERK1/2 that confer resistance to either ERK inhibitors or combined RAF/MEK inhibition in BRAF(V600)-mutant melanoma. Using a random mutagenesis screen, we identified multiple point mutations in ERK1 (MAPK3) and ERK2 (MAPK1) that could confer resistance to ERK or RAF/MEK inhibitors. ERK inhibitor-resistant alleles were sensitive to RAF/MEK inhibitors and vice versa, suggesting that the future development of alternating RAF/MEK and ERK inhibitor regimens might help circumvent resistance to these agents.
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts. Broad Institute, Cambridge, Massachusetts.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Goetz
authors.affiliation: Broad Institute, Cambridge, Massachusetts.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Ghandi
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Treacy
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts. Broad Institute, Cambridge, Massachusetts.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Wagle
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts. Broad Institute, Cambridge, Massachusetts. Levi_Garraway@dfci.harvard.edu.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics*; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics
chemical_list: D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases