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RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E).
Nature. 2011 Nov 23; 480(7377):387-90.Nat

Abstract

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.

Authors+Show Affiliations

Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22113612

Citation

Poulikakos, Poulikos I., et al. "RAF Inhibitor Resistance Is Mediated By Dimerization of Aberrantly Spliced BRAF(V600E)." Nature, vol. 480, no. 7377, 2011, pp. 387-90.
Poulikakos PI, Persaud Y, Janakiraman M, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature. 2011;480(7377):387-90.
Poulikakos, P. I., Persaud, Y., Janakiraman, M., Kong, X., Ng, C., Moriceau, G., Shi, H., Atefi, M., Titz, B., Gabay, M. T., Salton, M., Dahlman, K. B., Tadi, M., Wargo, J. A., Flaherty, K. T., Kelley, M. C., Misteli, T., Chapman, P. B., Sosman, J. A., ... Solit, D. B. (2011). RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature, 480(7377), 387-90. https://doi.org/10.1038/nature10662
Poulikakos PI, et al. RAF Inhibitor Resistance Is Mediated By Dimerization of Aberrantly Spliced BRAF(V600E). Nature. 2011 Nov 23;480(7377):387-90. PubMed PMID: 22113612.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). AU - Poulikakos,Poulikos I, AU - Persaud,Yogindra, AU - Janakiraman,Manickam, AU - Kong,Xiangju, AU - Ng,Charles, AU - Moriceau,Gatien, AU - Shi,Hubing, AU - Atefi,Mohammad, AU - Titz,Bjoern, AU - Gabay,May Tal, AU - Salton,Maayan, AU - Dahlman,Kimberly B, AU - Tadi,Madhavi, AU - Wargo,Jennifer A, AU - Flaherty,Keith T, AU - Kelley,Mark C, AU - Misteli,Tom, AU - Chapman,Paul B, AU - Sosman,Jeffrey A, AU - Graeber,Thomas G, AU - Ribas,Antoni, AU - Lo,Roger S, AU - Rosen,Neal, AU - Solit,David B, Y1 - 2011/11/23/ PY - 2011/05/04/received PY - 2011/10/20/accepted PY - 2011/11/25/entrez PY - 2011/11/25/pubmed PY - 2012/2/24/medline SP - 387 EP - 90 JF - Nature JO - Nature VL - 480 IS - 7377 N2 - 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. SN - 1476-4687 UR - https://www.unboundmedicine.com/medline/citation/22113612/RAF_inhibitor_resistance_is_mediated_by_dimerization_of_aberrantly_spliced_BRAF_V600E__ L2 - https://doi.org/10.1038/nature10662 DB - PRIME DP - Unbound Medicine ER -