Dimerization of BRAF V600E splice variants contributes to BRAF inhibitor resistance

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Homo sapiens
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RAF kinase inhibitors such as vemurafenib are clinically approved for treatment of BRAF-driven melanomas. Despite initial positive response to drug treatment, however, many tumors go on to develop resistance to the RAF inhibitors (Flaherty et al, 2010; Chapman et al, 2011; Sosman et al, 2012; Solit et al, 2011; reviewed in Lito et al, 2013). One mechanism that contributes to acquired resistance to RAF inhibitors is the expression of a splice variant of V600E that lacks the N-terminal RAS-binding domain. This variant displays increased RAS-independent dimerization and increased signaling relative to the full-length V600E, consistent with the notion that it is the monomeric form of BRAF that is sensitive to inhibition. Disruption of the dimer interface in this p61-V600E splice variant restores sensitivity to inhibition (Poulikakos et al, 2011; reviewed in Lito et al, 2013).
Other mechanisms of BRAF inhibitor resistance include mutational activation of NRAS or receptor tyrosine kinases, inactivation of the GAP protein NF1, or increased expression of RAF1 or BRAF (Nazarian et al, 2010; Maertens et al, 2013; Whittaker et al, 2013; Shi et al, 2012; Montagut et al, 2008; reviewed in Chapman, 2013; Lito et al, 2013).

Literature References
PubMed ID Title Journal Year
23171796 Elucidating distinct roles for NF1 in melanomagenesis

Granter, S, Cichowski, K, Johnson, B, Messiaen, L, Cooper, ZA, Wargo, JA, Flaherty, K, Frederick, DT, Bronson, RT, McMahon, M, Hollstein, P, Marais, R, Maertens, O

Cancer Discov 2013
22356324 Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib

Sosman, JA, Amaravadi, RK, McArthur, GA, Lewis, KD, Li, J, Shyr, Y, Gonzalez, R, Schuchter, L, Flaherty, KT, Lee, RJ, Lawrence, D, Lawrence, HJ, Kim, KB, Weber, JS, Puzanov, I, Ye, F, Ribas, A, Nolop, KB, Kefford, R, Pavlick, AC, Hutson, TE, Joe, AK, Chmielowski, B, Hersey, P, Moschos, SJ

N. Engl. J. Med. 2012
21639808 Improved survival with vemurafenib in melanoma with BRAF V600E mutation

Lorigan, P, Sosman, JA, Maio, M, Haanen, JB, McArthur, GA, Li, J, Garbe, C, Lebbe, C, Flaherty, KT, Hogg, D, Lee, RJ, Schadendorf, D, Robert, C, Larkin, J, Dummer, R, Eggermont, AM, Kirkwood, JM, Ribas, A, Jouary, T, O'Day, SJ, Dreno, B, Nelson, B, Chapman, PB, Nolop, K, Ascierto, P, Hauschild, A, Testori, A, Hou, J

N. Engl. J. Med. 2011
20818844 Inhibition of mutated, activated BRAF in metastatic melanoma

Kim, KB, Chapman, PB, Puzanov, I, Sosman, JA, Flaherty, KT, Lee, RJ, Ribas, A, Nolop, K, McArthur, GA, O'Dwyer, PJ, Grippo, JF

N. Engl. J. Med. 2010
22395615 Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance

Dahlman, KB, Sosman, JA, Lee, H, Kong, X, Kefford, RF, Ribas, A, Koya, RC, Chodon, T, Nelson, SF, Shi, H, Lo, RS, Long, GV, Scolyer, RA, Ng, C, Lee, MK, Moriceau, G

Nat Commun 2012
23288408 A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition

Hsiao, J, Whittaker, SR, Schadendorf, D, Van Allen, E, Wagle, N, Root, DE, Garraway, LA, Cowley, GS, Theurillat, JP

Cancer Discov 2013
21107323 Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation

Sosman, JA, Lee, H, McArthur, G, Kong, X, Ribas, A, Koya, RC, Chodon, T, Nelson, SF, Shi, H, Lo, RS, Wang, Q, Lee, MK, Chen, Z, Attar, N, Nazarian, R, Sazegar, H

Nature 2010
24202393 Tumor adaptation and resistance to RAF inhibitors

Lito, P, Solit, DB, Rosen, N

Nat. Med. 2013
22113612 RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E)

Graeber, TG, Dahlman, KB, Persaud, Y, Sosman, JA, Kong, X, Ribas, A, Gabay, MT, Shi, H, Lo, RS, Poulikakos, PI, Wargo, JA, Kelley, MC, Misteli, T, Chapman, PB, Titz, B, Flaherty, KT, Janakiraman, M, Ng, C, Tadi, M, Moriceau, G, Atefi, M, Solit, DB, Rosen, N, Salton, M

Nature 2011
18559533 Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma

Singh, A, Dias-Santagata, D, Sharma, SV, Haber, DA, Shioda, T, Lee, DY, McDermott, U, Ulkus, LE, Ulman, M, Settleman, J, Drew, L, Montagut, C, Stubbs, H

Cancer Res. 2008
Functional status

Gain of function of V600E BRAF splice variants [cytosol]

Disease Entity
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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