Reactome | Dimerization of BRAF V600E splice variants contributes to BRAF inhibitor resistance

Dimerization of BRAF V600E splice variants contributes to BRAF inhibitor resistance

Stable Identifier

R-HSA-6802930

Type

Reaction [binding]

Species

Homo sapiens

Compartment

cytosol

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Dimerization of BRAF V600E splice variants contributes to BRAF inhibitor resistance

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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
22356324	Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib Sosman, JA, Kim, KB, Schuchter, L, Gonzalez, R, Pavlick, AC, Weber, JS, McArthur, GA, Hutson, TE, Moschos, SJ, Flaherty, KT, Hersey, P, Kefford, R, Lawrence, D, Puzanov, I, Lewis, KD, Amaravadi, RK, Chmielowski, B, Lawrence, HJ, Shyr, Y, Ye, F, Li, J, Nolop, KB, Lee, RJ, Joe, AK, Ribas, A	N. Engl. J. Med.	2012
23171796	Elucidating distinct roles for NF1 in melanomagenesis Maertens, O, Johnson, B, Hollstein, P, Frederick, DT, Cooper, ZA, Messiaen, L, Bronson, RT, McMahon, M, Granter, S, Flaherty, K, Wargo, JA, Marais, R, Cichowski, K	Cancer Discov	2013
21639808	Improved survival with vemurafenib in melanoma with BRAF V600E mutation Chapman, PB, Hauschild, A, Robert, C, Haanen, JB, Ascierto, P, Larkin, J, Dummer, R, Garbe, C, Testori, A, Maio, M, Hogg, D, Lorigan, P, Lebbe, C, Jouary, T, Schadendorf, D, Ribas, A, O'Day, SJ, Sosman, JA, Kirkwood, JM, Eggermont, AM, Dreno, B, Nolop, K, Li, J, Nelson, B, Hou, J, Lee, RJ, Flaherty, KT, McArthur, GA	N. Engl. J. Med.	2011
20818844	Inhibition of mutated, activated BRAF in metastatic melanoma Flaherty, KT, Puzanov, I, Kim, KB, Ribas, A, McArthur, GA, Sosman, JA, O'Dwyer, PJ, Lee, RJ, Grippo, JF, Nolop, K, Chapman, PB	N. Engl. J. Med.	2010
22395615	Melanoma whole-exome sequencing identifies (V600E)B-RAF amplification-mediated acquired B-RAF inhibitor resistance Shi, H, Moriceau, G, Kong, X, Lee, MK, Lee, H, Koya, RC, Ng, C, Chodon, T, Scolyer, RA, Dahlman, KB, Sosman, JA, Kefford, RF, Long, GV, Nelson, SF, Ribas, A, Lo, RS	Nat Commun	2012
23288408	A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition Whittaker, SR, Theurillat, JP, Van Allen, E, Wagle, N, Hsiao, J, Cowley, GS, Schadendorf, D, Root, DE, Garraway, LA	Cancer Discov	2013
21107323	Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation Nazarian, R, Shi, H, Wang, Q, Kong, X, Koya, RC, Lee, H, Chen, Z, Lee, MK, Attar, N, Sazegar, H, Chodon, T, Nelson, SF, McArthur, G, Sosman, JA, Ribas, A, Lo, RS	Nature	2010
24202393	Tumor adaptation and resistance to RAF inhibitors Lito, P, Rosen, N, Solit, DB	Nat. Med.	2013
22113612	RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E) Poulikakos, PI, Persaud, Y, Janakiraman, M, Kong, X, Ng, C, Moriceau, G, Shi, H, Atefi, M, Titz, B, Gabay, MT, Salton, M, Dahlman, KB, Tadi, M, Wargo, JA, Flaherty, KT, Kelley, MC, Misteli, T, Chapman, PB, Sosman, JA, Graeber, TG, Ribas, A, Lo, RS, Rosen, N, Solit, DB	Nature	2011
18559533	Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma Montagut, C, Sharma, SV, Shioda, T, McDermott, U, Ulman, M, Ulkus, LE, Dias-Santagata, D, Stubbs, H, Lee, DY, Singh, A, Drew, L, Haber, DA, Settleman, J	Cancer Res.	2008