RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E)
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
BRAF inhibitors have proven ineffective as single agents due to adaptive feedback re-activation of the MAPK and other signaling pathways.
“BRAF inhibitors have proven ineffective as single agents due to adaptive feedback re-activation of the MAPK and other signaling pathways [5–13, 38].”
From Co-targeting SRC overcomes resistance to BRAF inhibitors in colorectal cancer (2025) · cites this paper as [12]
The Abstract (page not provided) reports that resistance to vemurafenib develops and that resistant cells can retain ERK signaling. But it describes RAF inhibitors as having remarkable clinical activity in BRAF(V600E) melanoma, not as ineffective single agents; its identified resistance mechanism is aberrant BRAF splicing and dimerization, not adaptive feedback reactivation of MAPK and other pathways. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Inhibition of Mutated, Activated BRAF in Metastatic Melanoma
Flaherty, K. T., Puzanov, I. J., Kim, K. B., Ribas, A., McArthur, G. A., Sosman, J. A., O'Dwyer, P. J., Lee, R. J., Grippo, J. F., Nolop, K. B., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1002011 · Cited by 3,542 · see citing works
Self-citationMelanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation
Nazarian, R., Shi, H., Wang, Q., Kong, X., Koya, R. C., Lee, H., Chen, Z., Lee, M., Attar, N., Sazegar, H., et al. (2010) · Nature · doi:10.1038/nature09626 · Cited by 2,198 · see citing works
Self-citationClinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma
Bollag, G. E., Hirth, P., Tsai, J. Y., Zhang, J., Ibrahim, P. N., Cho, H., Spevak, W. R., Zhang, C., Zhang, Y., Habets, G. G. M., et al. (2010) · Nature · doi:10.1038/nature09454 · Cited by 1,841 · see citing works
Self-citationRAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF
Poulikakos, P. I., Zhang, C., Bollag, G. E., Shokat, K. M., & Rosen, N. X. (2010) · Nature · doi:10.1038/nature08902 · Cited by 1,818 · see citing works
Self-citationRAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth
Hatzivassiliou, G., Song, K. W., Yen, I., Brandhuber, B. J., Anderson, D. J., Alvarado, R., Ludlam, M. J. C., Stokoe, D., Gloor, S. L., Vigers, G. P. A., et al. (2010) · Nature · doi:10.1038/nature08833 · Cited by 1,614 · see citing works
Kinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF
Heidorn, S. J., Milagre, C. S., Whittaker, S. R., Nourry, A., Niculescu‐Duvaz, I., Dhomen, N. S., Hussain, J., Reis-Filho, J. S., Springer, C. J., Pritchard, C. A., et al. (2010) · Cell · doi:10.1016/j.cell.2009.12.040 · Cited by 1,468 · see citing works
COT drives resistance to RAF inhibition through MAP kinase pathway reactivation
Johannessen, C. M., Boehm, J. S., Kim, S. Y., Thomas, S. R., Wardwell, L., Johnson, L. A., Emery, C. M., Stransky, N., Cogdill, A. P., Barretina, J., et al. (2010) · Nature · doi:10.1038/nature09627 · Cited by 1,460 · see citing works
Self-citationBRAF mutation predicts sensitivity to MEK inhibition
Solit, D. B., Garraway, L. A., Pratilas, C. A., Sawai, A., Getz, G. A., Basso, A., Ye, Q., Lobo, J. M., She, Y., Osman, I., et al. (2005) · Nature · doi:10.1038/nature04304 · Cited by 1,329 · see citing works
Self-citationVillanueva, J., Vultur, A., Lee, J. T., Somasundaram, R., Fukunaga‐Kalabis, M., Cipolla, A. K., Wubbenhorst, B. S., Xu, X., Gimotty, P. A., Kee, D., et al. (2010) · Cancer Cell · doi:10.1016/j.ccr.2010.11.023 · Cited by 1,261 · see citing works
Self-citationThe RAF proteins take centre stage
Wellbrock, C., Karasarides, M., & Marais, R. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1498 · Cited by 1,233 · see citing works
Dissecting Therapeutic Resistance to RAF Inhibition in Melanoma by Tumor Genomic Profiling
Wagle, N., Emery, C., Berger, M. F., Davis, M. J., Sawyer, A. M., Pochanard, P., Kehoe, S. M., Johannessen, C. M., MacConaill, L. E., Hahn, W. C., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.33.2312 · Cited by 996 · see citing works
Epigenetics in Alternative Pre-mRNA Splicing
Luco, R. F., Alló, M., Schor, I. E., Kornblihtt, A. R., & Misteli, T. (2011) · Cell · doi:10.1016/j.cell.2010.11.056 · Cited by 783 · see citing works
Self-citationA dimerization-dependent mechanism drives RAF catalytic activation
Rajakulendran, T., Sahmi, M., Lefrançois, M., Sicheri, F., & Therrien, M. (2009) · Nature · doi:10.1038/nature08314 · Cited by 492 · see citing works
Joseph, E. W., Pratilas, C. A., Poulikakos, P. I., Tadi, M., Wang, W., Taylor, B. S., Halilovic, E., Persaud, Y., Xing, F., Viale, A. J., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1008990107 · Cited by 450 · see citing works
Self-citationRegulation and Role of Raf-1/B-Raf Heterodimerization
Rushworth, L. K., Hindley, A. D., O’Neill, E. E., & Kölch, W. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.6.2262-2272.2006 · Cited by 419 · see citing works
Active Ras induces heterodimerization of cRaf and BRaf.
Weber, C., Slupsky, J. R., Kalmes, H. A., & Rapp, U. R. (2001) · PubMed · Cited by 312 · see citing works
Genomic and Biological Characterization of Exon 4 KRAS Mutations in Human Cancer
Janakiraman, M., Vakiani, E., Zeng, Z., Pratilas, C. A., Taylor, B. S., Chitale, D., Halilovic, E., Wilson, M., Huberman, K., Ricarte Filho, J. C., et al. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0192 · Cited by 290 · see citing works
Self-citationMutant BRAF Melanomas—Dependence and Resistance
Poulikakos, P. I., & Rosen, N. X. (2011) · Cancer Cell · doi:10.1016/j.ccr.2011.01.008 · Cited by 250 · see citing works
Self-citationAutoregulation of the Raf-1 serine/threonine kinase
Cutler, R. E., Stephens, R. M., Saracino, M. R., & Morrison, D. K. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.16.9214 · Cited by 200 · see citing works
Gatekeeper Mutations Mediate Resistance to BRAF-Targeted Therapies
Whittaker, S. R., Kirk, R., Hayward, R., Zambon, A., Virós, A., Cantariño, N., Affolter, A., Nourry, A., Niculescu‐Duvaz, D., Springer, C. J., et al. (2010) · Science Translational Medicine · doi:10.1126/scitranslmed.3000758 · Cited by 156 · see citing works
Nüsse, M., Beisker, W., Hoffmann, C., & Tárnok, A. (1990) · Cytometry · doi:10.1002/cyto.990110707 · Cited by 88 · see citing works
McArthur, G. A., Ribas, A., Chapman, P. B., Flaherty, K. T., Kim, K. B., Puzanov, I. J., Nathanson, K. L., Lee, R. J., Koehler, A., Spleiss, O., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.29.15_suppl.8502 · Cited by 40 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Zehir, A., Benayed, R., Shah, R. H., Syed, A., Middha, S., Kim, H. R., Srinivasan, P., Gao, J., Chakravarty, D., Devlin, S. M., et al. (2017) · Nature Medicine · doi:10.1038/nm.4333 · Cited by 3,380 · see citing works
Self-citationCombined BRAF and MEK inhibition in melanoma with BRAF V600 mutations
Flaherty, K. T., Infante, J. R., Daud, A., Gonzalez, R., Kefford, R. F., Sosman, J., Hamid, O., Schuchter, L., Cebon, J., Ibrahim, N., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1210093 · Cited by 2,810 · see citing works
Self-citationSurvival in BRAF V600-mutant advanced melanoma treated with vemurafenib
Sosman, J. A., Kim, K. B., Schuchter, L., Gonzalez, R., Pavlick, A. C., Weber, J. S., McArthur, G. A., Hutson, T. E., Moschos, S. J., Flaherty, K. T., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1112302 · Cited by 2,156 · see citing works
Self-citationTumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion
Straussman, R., Morikawa, T., Shee, K., Barzily-Rokni, M., Qian, Z. R., Du, J., Davis, A., Mongare, M. M., Gould, J., Frederick, D. T., et al. (2012) · Nature · doi:10.1038/nature11183 · Cited by 1,771 · see citing works
Self-citationTargeting RAS–ERK signalling in cancer: promises and challenges
Samatar, A. A., & Poulikakos, P. I. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4281 · Cited by 1,163 · see citing works
Self-citationCombinatorial drug therapy for cancer in the post-genomic era
Al-Lazikani, B., Banerji, U., & Workman, P. (2012) · Nature Biotechnology · doi:10.1038/nbt.2284 · Cited by 1,070 · see citing works
Mechanisms of receptor tyrosine kinase activation in cancer
Du, Z., & Lovly, C. M. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0782-4 · Cited by 1,066 · see citing works
The landscape of kinase fusions in cancer
Stransky, N., Cerami, E., Schalm, S., Kim, J. L., & Lengauer, C. (2014) · Nature Communications · doi:10.1038/ncomms5846 · Cited by 968 · see citing works
Acquired Resistance and Clonal Evolution in Melanoma during BRAF Inhibitor Therapy
Shi, H., Hugo, W., Kong, X., Hong, A., Koya, R. C., Moriceau, G., Chodon, T., Guo, R., Johnson, D. B., Dahlman, K. B., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0642 · Cited by 982 · see citing works
Self-citationReversible and adaptive resistance to BRAF(V600E) inhibition in melanoma
Sun, C., Wang, L., Huang, S., Heynen, G. J. J. E., Prahallad, A., Robert, C., Haanen, J., Blank, C., Wesseling, J., Willems, S. M., et al. (2014) · Nature · doi:10.1038/nature13121 · Cited by 888 · see citing works
Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance
Das Thakur, M., Salangsang, F., Landman, A. S., Sellers, W. R., Pryer, N. K., Levesque, M. P., Dummer, R., McMahon, M., & Stuart, D. D. (2013) · Nature · doi:10.1038/nature11814 · Cited by 730 · see citing works
Morris, E. J., Jha, S., Restaino, C. R., Dayananth, P., Zhu, H., Cooper, A., Carr, D., Deng, Y., Jin, W., Black, S., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0070 · Cited by 676 · see citing works
Roesch, A., Vultur, A., Bogeski, I., Wang, H., Zimmermann, K. M., Speicher, D., Körbel, C., Laschke, M. W., Gimotty, P. A., Philipp, S. E., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.05.003 · Cited by 670 · see citing works
Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma
Müller, J., Krijgsman, O., Tsoi, J., Robert, L., Hugo, W., Song, C., Kong, X., Possik, P. A., Cornelissen-Steijger, P. D. M., Foppen, M. H. G., et al. (2014) · Nature Communications · doi:10.1038/ncomms6712 · Cited by 639 · see citing works
Self-citationHirata, E., Girotti, M. R., Viros, A., Hooper, S., Spencer-Dene, B., Matsuda, M., Larkin, J., Marais, R., & Sahai, E. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.03.008 · Cited by 593 · see citing works
Tumor adaptation and resistance to RAF inhibitors
Lito, P., Rosen, N., & Solit, D. B. (2013) · Nature Medicine · doi:10.1038/nm.3392 · Cited by 585 · see citing works
Self-citationTumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS
Yao, Z., Yaeger, R., Rodrik-Outmezguine, V. S., Tao, A., Torres, N. M., Chang, M. T., Drosten, M., Zhao, H., Cecchi, F., Hembrough, T., et al. (2017) · Nature · doi:10.1038/nature23291 · Cited by 562 · see citing works
Self-citationLito, P., Pratilas, C. A., Joseph, E. W., Tadi, M., Halilovic, E., Zubrowski, M., Huang, A., Wong, W. L., Callahan, M. K., Merghoub, T., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.10.009 · Cited by 562 · see citing works
Self-citationYao, Z., Torres, N. M., Tao, A., Gao, Y., Luo, L., Li, Q., de Stanchina, E., Abdel-Wahab, O., Solit, D. B., Poulikakos, P. I., et al. (2015) · Cancer Cell · doi:10.1016/j.ccell.2015.08.001 · Cited by 543 · see citing works
Self-citationRAF-MEK-ERK pathway in cancer evolution and treatment
Ullah, R., Yin, Q., Snell, A. H., & Wan, L. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.05.010 · Cited by 553 · see citing works
Circumventing cancer drug resistance in the era of personalized medicine
Garraway, L. A., & Jänne, P. A. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0012 · Cited by 503 · see citing works
Melanoma: from mutations to medicine
Tsao, H., Chin, L., Garraway, L. A., & Fisher, D. E. (2012) · Genes & Development · doi:10.1101/gad.191999.112 · Cited by 496 · see citing works
Mutant BRAF and MEK inhibitors regulate the tumor immune microenvironment via pyroptosis
Erkes, D. A., Cai, W., Sanchez, I. M., Purwin, T. J., Rogers, C., Field, C. O., Berger, A. C., Hartsough, E. J., Rodeck, U., Alnemri, E. S., et al. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-19-0672 · Cited by 459 · see citing works
Jiang, X., Zhou, J., Giobbie-Hurder, A., Wargo, J., & Hodi, F. S. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-2731 · Cited by 485 · see citing works
Self-citationWagle, N., Van Allen, E. M., Treacy, D. J., Frederick, D. T., Cooper, Z. A., Taylor-Weiner, A., Rosenberg, M., Goetz, E. M., Sullivan, R. J., Farlow, D. N., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0631 · Cited by 478 · see citing works
Self-citationThe role of tumour-stromal interactions in modifying drug response: challenges and opportunities
McMillin, D. W., Negri, J. M., & Mitsiades, C. S. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd3870 · Cited by 474 · see citing works
Targeting ER stress–induced autophagy overcomes BRAF inhibitor resistance in melanoma
Ma, X.-H., Piao, S.-F., Dey, S., Mcafee, Q., Karakousis, G., Villanueva, J., Hart, L. S., Levi, S., Hu, J., Zhang, G., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci70454 · Cited by 457 · see citing works
Nichols, R. J., Haderk, F., Stahlhut, C., Schulze, C. J., Hemmati, G., Wildes, D., Tzitzilonis, C., Mordec, K., Marquez, A., Romero, J., et al. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0169-1 · Cited by 415 · see citing works
New perspectives for targeting RAF kinase in human cancer
Karoulia, Z., Gavathiotis, E., & Poulikakos, P. I. (2017) · Nature Reviews Cancer · doi:10.1038/nrc.2017.79 · Cited by 404 · see citing works
Self-citationMontero-Conde, C., Ruiz-Llorente, S., Dominguez, J. M., Knauf, J. A., Viale, A., Sherman, E. J., Ryder, M., Ghossein, R. A., Rosen, N., & Fagin, J. A. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0531 · Cited by 382 · see citing works
Self-citationLong, G. V., Fung, C., Menzies, A. M., Pupo, G. M., Carlino, M. S., Hyman, J., Shahheydari, H., Tembe, V., Thompson, J. F., Saw, R. P., et al. (2014) · Nature Communications · doi:10.1038/ncomms6694 · Cited by 375 · see citing works
Ras-GTP dimers activate the Mitogen-Activated Protein Kinase (MAPK) pathway
Nan, X., Tamgüney, T. M., Collisson, E. A., Lin, L.-J., Pitt, C., Galeas, J., Lewis, S., Gray, J. W., McCormick, F., & Chu, S. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1509123112 · Cited by 273 · see citing works
Kakadia, S., Yarlagadda, N., Awad, R., Kundranda, M., Niu, J., Naraev, B., Mina, L., Dragovich, T., Gimbel, M., & Mahmoud, F. (2018) · OncoTargets and Therapy · doi:10.2147/ott.s182721 · Cited by 277 · see citing works
A Convergence-Based Framework for Cancer Drug Resistance
Konieczkowski, D. J., Johannessen, C. M., & Garraway, L. A. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.03.025 · Cited by 258 · see citing works
Misale, S., Arena, S., Lamba, S., Siravegna, G., Lallo, A., Hobor, S., Russo, M., Buscarino, M., Lazzari, L., Sartore-Bianchi, A., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3007947 · Cited by 263 · see citing works
Targeting RAS–RAF–MEK–ERK signaling pathway in human cancer: Current status in clinical trials
Song, Y., Bi, Z., Liu, Y., Qin, F., Wei, Y., & Wei, X. (2023) · Genes & Diseases · doi:10.1016/j.gendis.2022.05.006 · Cited by 212 · see citing works
Yadav, V., Zhang, X., Liu, J., Estrem, S., Li, S., Gong, X.-Q., Buchanan, S., Henry, J. R., Starling, J. J., & Peng, S.-B. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.377218 · Cited by 200 · see citing works
Yao, Z., Gao, Y., Su, W., Yaeger, R., Tao, J., Na, N., Zhang, Y., Zhang, C., Rymar, A., Tao, A., et al. (2019) · Nature Medicine · doi:10.1038/s41591-018-0274-5 · Cited by 195 · see citing works
Self-citationPencheva, N., Buss, C. G., Posada, J., Merghoub, T., & Tavazoie, S. F. (2014) · Cell · doi:10.1016/j.cell.2014.01.038 · Cited by 175 · see citing works
An approach to suppress the evolution of resistance in BRAFV600E-mutant cancer
Xue, Y., Martelotto, L., Baslan, T., Vides, A., Solomon, M., Mai, T. T., Chaudhary, N., Riely, G. J., Li, B. T., Scott, K., et al. (2017) · Nature Medicine · doi:10.1038/nm.4369 · Cited by 174 · see citing works
Self-citationChen, S.-H., Zhang, Y., Van Horn, R. D., Yin, T., Buchanan, S., Yadav, V., Mochalkin, I., Wong, S. S., Yue, Y. G., Huber, L., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-0896 · Cited by 171 · see citing works
Molecular Pathways and Mechanisms of BRAF in Cancer Therapy
Poulikakos, P. I., Sullivan, R. J., & Yaeger, R. (2022) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-2138 · Cited by 145 · see citing works
Self-citationMutant-selective degradation by BRAF-targeting PROTACs
Alabi, S., Jaime-Figueroa, S., Yao, Z., Gao, Y., Hines, J., Samarasinghe, K. T. G., Vogt, L., Rosen, N., & Crews, C. M. (2021) · Nature Communications · doi:10.1038/s41467-021-21159-7 · Cited by 152 · see citing works
Self-citationTORC1 Suppression Predicts Responsiveness to RAF and MEK Inhibition in <i>BRAF-</i> Mutant Melanoma
Corcoran, R. B., Rothenberg, S. M., Hata, A. N., Faber, A. C., Piris, A., Nazarian, R. M., Brown, R. D., Godfrey, J. T., Winokur, D., Walsh, J., et al. (2013) · Science Translational Medicine · doi:10.1126/scitranslmed.3005753 · Cited by 140 · see citing works
Self-citationARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma
Yen, I., Shanahan, F., Lee, J., Hong, Y. S., Shin, S. J., Moore, A. R., Sudhamsu, J., Chang, M. T., Bae, I., Dela Cruz, D., et al. (2021) · Nature · doi:10.1038/s41586-021-03515-1 · Cited by 138 · see citing works
Yadav, V., Burke, T. F., Huber, L., Van Horn, R. D., Zhang, Y., Buchanan, S. G., Chan, E. M., Starling, J. J., Beckmann, R. P., & Peng, S.-B. (2014) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-0257 · Cited by 132 · see citing works
BRAF — a tumour-agnostic drug target with lineage-specific dependencies
Hanrahan, A. J., Chen, Z., Rosen, N., & Solit, D. B. (2024) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-023-00852-0 · Cited by 136 · see citing works
Self-citationJohnson, G. L., Stuhlmiller, T. J., Angus, S. P., Zawistowski, J. S., & Graves, L. M. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-1081 · Cited by 129 · see citing works
Combination of Immunotherapy With Targeted Therapy: Theory and Practice in Metastatic Melanoma
Yu, C., Liu, X., Yang, J., Zhang, M., Jin, H., Ma, X., & Shi, H. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00990 · Cited by 126 · see citing works
Self-citationHarnessing the predictive power of preclinical models for oncology drug development
Honkala, A., Malhotra, S. V., Kummar, S., & Junttila, M. R. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00301-6 · Cited by 121 · see citing works
Fallahi‐Sichani, M., Moerke, N. J., Niepel, M., Zhang, T., Gray, N. S., & Sorger, P. K. (2015) · Molecular Systems Biology · doi:10.15252/msb.20145877 · Cited by 99 · see citing works
Resistance is futile: overcoming resistance to targeted therapies in lung adenocarcinoma
Neel, D. S., & Bivona, T. G. (2017) · npj Precision Oncology · doi:10.1038/s41698-017-0007-0 · Cited by 98 · see citing works
Yaeger, R., Yao, Z., Hyman, D. M., Hechtman, J. F., Vakiani, E., Zhao, H., Su, W., Wang, L., Joelson, A., Cercek, A., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-17-0768 · Cited by 94 · see citing works
Self-citationSynthetic Lethal Interaction of SHOC2 Depletion with MEK Inhibition in RAS-Driven Cancers
Sulahian, R., Kwon, J. J., Walsh, K. H., Pailler, E., Bosse, T. L., Thaker, M., Almanza, D., Dempster, J. M., Pan, J., Piccioni, F., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.08.090 · Cited by 90 · see citing works
MEK inhibition in non-small cell lung cancer
Stinchcombe, T. E., & Johnson, G. L. (2014) · Lung Cancer · doi:10.1016/j.lungcan.2014.09.005 · Cited by 69 · see citing works
“Pathway drug cocktail”: targeting Ras signaling based on structural pathways
Nussinov, R., Tsai, C.-J., & Mattos, C. (2013) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2013.07.009 · Cited by 62 · see citing works
Deuker, M. M., Marsh Durban, V., Phillips, W. A., & McMahon, M. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0856 · Cited by 60 · see citing works
Sale, M. J., & Cook, S. J. (2013) · Biochemical Journal · doi:10.1042/bj20121212 · Cited by 58 · see citing works
Kholodenko, B. N. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.08.014 · Cited by 49 · see citing works
Berman, E., Jhanwar, S., Hedvat, C., Arcila, M. E., Wahab, O. A., Levine, R., Maloy, M., Ma, W., & Albitar, M. (2016) · Leukemia Research · doi:10.1016/j.leukres.2016.08.006 · Cited by 41 · see citing works
Embryonal Fyn-associated substrate (EFS) and CASS4: The lesser-known CAS protein family members
Deneka, A., Korben, V. A., & Golemis, E. A. (2015) · Gene · doi:10.1016/j.gene.2015.06.062 · Cited by 33 · see citing works
Hartsough, E. J., Kugel, C. H., Vido, M. J., Berger, A. C., Purwin, T. J., Goldberg, A., Davies, M. A., Schiewer, M. J., Knudsen, K. E., Bollag, G., et al. (2018) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-17-0705 · Cited by 27 · see citing works
Co-targeting SRC overcomes resistance to BRAF inhibitors in colorectal cancer
Rubio-Cuesta, B., Carretero-Puche, C., Llamas, P., Sarmentero, J., Gil-Calderon, B., Lens-Pardo, A., Antón-Pascual, B., Rubio-González, E., Cámara-Jurado, M., Salamanca, J., et al. (2025) · British Journal of Cancer · doi:10.1038/s41416-025-03058-6 · Cited by 7 · see citing works
- Authors
- 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., Graeber, T. G., Ribas, A., Lo, R. S., Rosen, N., & Solit, D. B.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- University of California, Los Angeles (US)
- National Institutes of Health (US)
- Vanderbilt University (US)
- Massachusetts General Hospital (US)
- Corresponding author
- Solit, David B.
- ORCID
- Venue
- Nature
- Published
- 2011-11-23
- Volume
- 480
- Issue
- 7377
- Pages
- 387-390
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3266695
- OpenAlex
- W2043058822
- Cited by
- 1,454
- References
- 22
- Citations by year
- 2026: 35 · 2025: 41 · 2024: 60 · 2023: 60 · 2022: 65 · 2021: 72 · 2020: 96 · 2019: 108 · 2018: 100 · 2017: 122 · 2016: 97 · 2015: 142 · 2014: 166 · 2013: 167 · 2012: 118
- FWCI
- 59.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health
- U.S. Public Health Service (T32 CACA062948-15)
- National Cancer Institute (K22CA151638, R01CA127240, T32CA062948, P30CA008748)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- RAF inhibitors, BRAF V600E mutation, melanoma, vemurafenib, Raf kinase inhibitor, alternative splicing, protein dimerization, Ras-binding domain, ERK signaling, acquired drug resistance, kinase inhibitor resistance, BRAF-mutant melanoma, Ras activation
- MeSH terms
- Vemurafenib, Animals, Exons, Humans, Indoles, Melanoma, Sulfonamides, Alternative Splicing, Drug Resistance, Neoplasm, Protein Isoforms, MAP Kinase Signaling System, Cell Line, Tumor, Protein Kinase Inhibitors, Extracellular Signal-Regulated MAP Kinases, Proto-Oncogene Proteins B-raf, Mutant Proteins, Mice, Protein Multimerization
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
