title: RAF inhibitors that evade paradoxical MAPK pathway activation.
abstract: Oncogenic activation of BRAF fuels cancer growth by constitutively promoting RAS-independent mitogen-activated protein kinase (MAPK) pathway signalling. Accordingly, RAF inhibitors have brought substantially improved personalized treatment of metastatic melanoma. However, these targeted agents have also revealed an unexpected consequence: stimulated growth of certain cancers. Structurally diverse ATP-competitive RAF inhibitors can either inhibit or paradoxically activate the MAPK pathway, depending whether activation is by BRAF mutation or by an upstream event, such as RAS mutation or receptor tyrosine kinase activation. Here we have identified next-generation RAF inhibitors (dubbed 'paradox breakers') that suppress mutant BRAF cells without activating the MAPK pathway in cells bearing upstream activation. In cells that express the same HRAS mutation prevalent in squamous tumours from patients treated with RAF inhibitors, the first-generation RAF inhibitor vemurafenib stimulated in vitro and in vivo growth and induced expression of MAPK pathway response genes; by contrast the paradox breakers PLX7904 and PLX8394 had no effect. Paradox breakers also overcame several known mechanisms of resistance to first-generation RAF inhibitors. Dissociating MAPK pathway inhibition from paradoxical activation might yield both improved safety and more durable efficacy than first-generation RAF inhibitors, a concept currently undergoing human clinical evaluation with PLX8394.
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Wayne
authors.initials: W
authors.lastname: Spevak
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Burton
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Gaston
authors.initials: G
authors.lastname: Habets
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Jiazhong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Lin
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Ewing
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Bernice
authors.initials: B
authors.lastname: Matusow
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Garson
authors.initials: G
authors.lastname: Tsang
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Adhirai
authors.initials: A
authors.lastname: Marimuthu
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Hanna
authors.initials: H
authors.lastname: Cho
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Guoxian
authors.initials: G
authors.lastname: Wu
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Weiru
authors.initials: W
authors.lastname: Wang
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fong
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Hoa
authors.initials: H
authors.lastname: Nguyen
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Songyuan
authors.initials: S
authors.lastname: Shi
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Womack
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Marika
authors.initials: M
authors.lastname: Nespi
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Rafe
authors.initials: R
authors.lastname: Shellooe
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Carias
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Powell
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Light
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Sanftner
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Walters
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: James
authors.initials: J
authors.lastname: Tsai
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Brian L
authors.initials: BL
authors.lastname: West
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Visor
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Hamid
authors.initials: H
authors.lastname: Rezaei
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Paul S
authors.initials: PS
authors.lastname: Lin
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Nolop
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Prabha N
authors.initials: PN
authors.lastname: Ibrahim
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Hirth
authors.affiliation: Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.
authors.forename: Gideon
authors.initials: G
authors.lastname: Bollag
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D011905:Genes, ras / Q000235:genetics; D006574:Heterocyclic Compounds, 2-Ring / Q000009:adverse effects / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D013449:Sulfonamides / Q000009:adverse effects / Q000494:pharmacology; D000077484:Vemurafenib
chemical_list: D006574:Heterocyclic Compounds, 2-Ring; D007211:Indoles; C000602641:PLX7904; C000602642:PLX8394; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases