Publication Date:
2015-10-16
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Chao -- Spevak, Wayne -- Zhang, Ying -- Burton, Elizabeth A -- Ma, Yan -- Habets, Gaston -- Zhang, Jiazhong -- Lin, Jack -- Ewing, Todd -- Matusow, Bernice -- Tsang, Garson -- Marimuthu, Adhirai -- Cho, Hanna -- Wu, Guoxian -- Wang, Weiru -- Fong, Daniel -- Nguyen, Hoa -- Shi, Songyuan -- Womack, Patrick -- Nespi, Marika -- Shellooe, Rafe -- Carias, Heidi -- Powell, Ben -- Light, Emily -- Sanftner, Laura -- Walters, Jason -- Tsai, James -- West, Brian L -- Visor, Gary -- Rezaei, Hamid -- Lin, Paul S -- Nolop, Keith -- Ibrahim, Prabha N -- Hirth, Peter -- Bollag, Gideon -- England -- Nature. 2015 Oct 22;526(7574):583-6. doi: 10.1038/nature14982. Epub 2015 Oct 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26466569" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cell Line, Tumor
;
Enzyme Activation/drug effects
;
Female
;
Genes, ras/genetics
;
Heterocyclic Compounds, 2-Ring/adverse effects/pharmacology
;
Humans
;
Indoles/adverse effects/pharmacology
;
MAP Kinase Signaling System/*drug effects/genetics
;
Mice
;
Mitogen-Activated Protein Kinases/*metabolism
;
Models, Biological
;
Mutation/genetics
;
Protein Kinase Inhibitors/adverse effects/*pharmacology
;
Proto-Oncogene Proteins B-raf/*antagonists & inhibitors/genetics
;
Sulfonamides/adverse effects/pharmacology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
