雖然最近的臨床試驗已經(jīng)表明了B-RAF抑制因子在治療有激發(fā)性B-RAF突變的黑素瘤中的有效性，但患者不可避免地會產(chǎn)生抵抗力,。
現(xiàn)在,，David Solit及其同事識別出B-RAF本身的結構變化所產(chǎn)生的獲得性抵抗力的一個機制。突變體B-RAF的一個“61千道爾頓剪接變體”的表達導致增強的B-RAF二聚作用,，使其對激酶抑制因子產(chǎn)生抵抗力,。這種變體過去曾被發(fā)現(xiàn)表達在對B-RAF 抑制因子PLX4032產(chǎn)生了抵抗力的19個患者的其中6個當中。（生物谷Bioon.com）
doi:10.1038/nature10662
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RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E)
Poulikos I. Poulikakos, Yogindra Persaud, Manickam Janakiraman, Xiangju Kong, Charles Ng, Gatien Moriceau, Hubing Shi, Mohammad Atefi, Bjoern Titz, May Tal Gabay, Maayan Salton, Kimberly B. Dahlman, Madhavi Tadi, Jennifer A. Wargo, Keith T. Flaherty, Mark C. Kelley, Tom Misteli, Paul B. Chapman, Jeffrey A. Sosman, Thomas G. Graeber, Antoni Ribas, Roger S. Lo, Neal Rosen, & David B. Solit
Activated RAS promotes dimerization of members of the RAF kinase family1, 2, 3. ATP-competitive RAF inhibitors activate ERK signalling4, 5, 6, 7 by transactivating RAF dimers4. 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.
