title: Disruption of CRAF-mediated MEK activation is required for effective MEK inhibition in KRAS mutant tumors.
abstract: MEK inhibitors are clinically active in BRAF(V600E) melanomas but only marginally so in KRAS mutant tumors. Here, we found that MEK inhibitors suppress ERK signaling more potently in BRAF(V600E), than in KRAS mutant tumors. To understand this, we performed an RNAi screen in a KRAS mutant model and found that CRAF knockdown enhanced MEK inhibition. MEK activated by CRAF was less susceptible to MEK inhibitors than when activated by BRAF(V600E). MEK inhibitors induced RAF-MEK complexes in KRAS mutant models, and disrupting such complexes enhanced inhibition of CRAF-dependent ERK signaling. Newer MEK inhibitors target MEK catalytic activity and also impair its reactivation by CRAF, either by disrupting RAF-MEK complexes or by interacting with Ser 222 to prevent MEK phosphorylation by RAF.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Piro
authors.initials: P
authors.lastname: Lito
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Saborowski
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Jingyin
authors.initials: J
authors.lastname: Yue
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Martha
authors.initials: M
authors.lastname: Solomon
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Joseph
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Sunyana
authors.initials: S
authors.lastname: Gadal
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Saborowski
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Kastenhuber
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Christof
authors.initials: C
authors.lastname: Fellmann
authors.affiliation: Research Division, Chugai Pharmaceutical, Kamakura, 247-8530, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ohara
authors.affiliation: Research Division, Chugai Pharmaceutical, Kamakura, 247-8530, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Morikami
authors.affiliation: Research Division, Chugai Pharmaceutical, Kamakura, 247-8530, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Miura
authors.affiliation: Roche Research Center, Hoffmann-La Roche, Nutley, NJ 07110, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Lukacs
authors.affiliation: Research Division, Chugai Pharmaceutical, Kamakura, 247-8530, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Ishii
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, New York, NY 10065, USA. Electronic address: lowes@mskcc.org.
authors.forename: Scott
authors.initials: S
authors.lastname: Lowe
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA; Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. Electronic address: rosenn@mskcc.org.
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D003374:Coumarins / Q000494:pharmacology; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D013449:Sulfonamides / Q000494:pharmacology; D020349:Surface Plasmon Resonance; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics* / Q000378:metabolism; D000077484:Vemurafenib; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics*
chemical_list: D001549:Benzamides; D003374:Coumarins; D007211:Indoles; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011728:Pyridones; D011744:Pyrimidinones; D034741:RNA, Small Interfering; C577924:RO5126766; D013449:Sulfonamides; D048008:TNF Receptor-Associated Factor 3; D000077484:Vemurafenib; C560077:trametinib; C506614:mirdametinib; D004159:Diphenylamine; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
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