Publication Date:
2011-11-25
Description:
Activated RAS promotes dimerization of members of the RAF kinase family. ATP-competitive RAF inhibitors activate ERK signalling by transactivating RAF dimers. In melanomas with mutant BRAF(V600E), levels of RAS activation are low and these drugs bind to BRAF(V600E) monomers and inhibit their activity. This tumour-specific inhibition of ERK signalling results in a broad therapeutic index and RAF inhibitors have remarkable clinical activity in patients with melanomas that harbour mutant BRAF(V600E). However, resistance invariably develops. Here, we identify a new resistance mechanism. We find that a subset of cells resistant to vemurafenib (PLX4032, RG7204) express a 61-kDa variant form of BRAF(V600E), p61BRAF(V600E), which lacks exons 4-8, a region that encompasses the RAS-binding domain. p61BRAF(V600E) shows enhanced dimerization in cells with low levels of RAS activation, as compared to full-length BRAF(V600E). In cells in which p61BRAF(V600E) is expressed endogenously or ectopically, ERK signalling is resistant to the RAF inhibitor. Moreover, a mutation that abolishes the dimerization of p61BRAF(V600E) restores its sensitivity to vemurafenib. Finally, we identified BRAF(V600E) splicing variants lacking the RAS-binding domain in the tumours of six of nineteen patients with acquired resistance to vemurafenib. These data support the model that inhibition of ERK signalling by RAF inhibitors is dependent on levels of RAS-GTP too low to support RAF dimerization and identify a novel mechanism of acquired resistance in patients: expression of splicing isoforms of BRAF(V600E) that dimerize in a RAS-independent manner.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266695/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266695/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Poulikakos, Poulikos I -- Persaud, Yogindra -- Janakiraman, Manickam -- Kong, Xiangju -- Ng, Charles -- Moriceau, Gatien -- Shi, Hubing -- Atefi, Mohammad -- Titz, Bjoern -- Gabay, May Tal -- Salton, Maayan -- Dahlman, Kimberly B -- Tadi, Madhavi -- Wargo, Jennifer A -- Flaherty, Keith T -- Kelley, Mark C -- Misteli, Tom -- Chapman, Paul B -- Sosman, Jeffrey A -- Graeber, Thomas G -- Ribas, Antoni -- Lo, Roger S -- Rosen, Neal -- Solit, David B -- K22 CA151638/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- R01 CA127240/CA/NCI NIH HHS/ -- R01 CA127240-01A1/CA/NCI NIH HHS/ -- T32 CACA062948-15/PHS HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2011 Nov 23;480(7377):387-90. doi: 10.1038/nature10662.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22113612" target="_blank"〉PubMed〈/a〉
Keywords:
Alternative Splicing/*genetics
;
Animals
;
Cell Line, Tumor
;
Drug Resistance, Neoplasm/drug effects/*genetics
;
Exons/genetics
;
Extracellular Signal-Regulated MAP Kinases/metabolism
;
Humans
;
Indoles/pharmacology
;
MAP Kinase Signaling System/drug effects
;
Melanoma/enzymology/metabolism/pathology
;
Mice
;
Mutant Proteins/chemistry/genetics/metabolism
;
Protein Isoforms/chemistry/genetics/metabolism
;
Protein Kinase Inhibitors/pharmacology
;
Protein Multimerization/drug effects/*genetics
;
Proto-Oncogene Proteins B-raf/antagonists &
;
inhibitors/chemistry/*genetics/*metabolism
;
Sulfonamides/pharmacology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink
