RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E)

被引：1135

作者：

Poulikakos, Poulikos I. ^{[2
]}

Persaud, Yogindra ^{[1
]}

Janakiraman, Manickam ^{[1
]}

Kong, Xiangju ^{[3
]}

Ng, Charles ^{[4
]}

Moriceau, Gatien ^{[3
]}

Shi, Hubing ^{[3
]}

Atefi, Mohammad ^{[4
]}

Titz, Bjoern ^{[5
]}

Gabay, May Tal ^{[2
]}

Salton, Maayan ^{[6
]}

Dahlman, Kimberly B. ^{[7
]}

Tadi, Madhavi ^{[2
]}

Wargo, Jennifer A. ^{[8
]}

Flaherty, Keith T. ^{[9
]}

Kelley, Mark C. ^{[10
]}

Misteli, Tom ^{[6
]}

Chapman, Paul B. ^{[11
]}

Sosman, Jeffrey A. ^{[7
]}

Graeber, Thomas G. ^{[5
]}

Ribas, Antoni ^{[4
,5
]}

Lo, Roger S. ^{[3
,5
]}

Rosen, Neal ^{[2
,11
]}

Solit, David B. ^{[1
,11
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[2] Mem Sloan Kettering Canc Ctr, Dept Mol Pharmacol & Chem, New York, NY 10065 USA

[3] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Dept Med, Div Dermatol, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Dept Med, Div Hematol & Oncol, Los Angeles, CA 90095 USA

[5] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA

[6] NCI, NIH, Bethesda, MD 20892 USA

[7] Vanderbilt Ingram Canc Ctr, Dept Med, Nashville, TN 37232 USA

[8] Massachusetts Gen Hosp, Ctr Canc, Dept Surg, Boston, MA 02114 USA

[9] Massachusetts Gen Hosp, Ctr Canc, Dept Med, Boston, MA 02114 USA

[10] Vanderbilt Ingram Canc Ctr, Dept Surg, Nashville, TN 37232 USA

[11] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA

来源：

NATURE | 2011年 / 480卷 / 7377期

基金：

美国国家卫生研究院;

关键词：

BRAF; PATHWAY; MEK;

D O I：

10.1038/nature10662

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Activated RAS promotes dimerization of members of the RAF kinase family(1-3). ATP-competitive RAF inhibitors activate ERK signalling(4-7) by transactivating RAF dimers(4). 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)(8). 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.

引用

页码：387 / U144

页数：5

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