Acquired Resistance and Clonal Evolution in Melanoma during BRAF Inhibitor Therapy
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Abstract
Abstract BRAF inhibitors elicit rapid antitumor responses in the majority of patients with BRAFV600-mutant melanoma, but acquired drug resistance is almost universal. We sought to identify the core resistance pathways and the extent of tumor heterogeneity during disease progression. We show that mitogen-activated protein kinase reactivation mechanisms were detected among 70% of disease-progressive tissues, with RAS mutations, mutant BRAF amplification, and alternative splicing being most common. We also detected PI3K–PTEN–AKT–upregulating genetic alterations among 22% of progressive melanomas. Distinct molecular lesions in both core drug escape pathways were commonly detected concurrently in the same tumor or among multiple tumors from the same patient. Beyond harboring extensively heterogeneous resistance mechanisms, melanoma regrowth emerging from BRAF inhibitor selection displayed branched evolution marked by altered mutational spectra/signatures and increased fitness. Thus, melanoma genomic heterogeneity contributes significantly to BRAF inhibitor treatment failure, implying upfront, cotargeting of two core pathways as an essential strategy for durable responses. Significance: This study provides critical insights into how human BRAF-mutant melanoma, a malignancy with marked mutational burden, escapes from BRAF inhibitors. Understanding the core resistance pathways as well as tumor heterogeneity, fitness, and mutational patterns, which emerge under drug selection, lays a foundation to rationalize clinical studies and investigate mechanisms of disease progression. Cancer Discov; 4(1); 80–93. ©2013 AACR. See related commentary by Solit and Rosen, p. 27 This article is highlighted in the In This Issue feature, p. 1
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In melanoma, core regulators of neural crest lineage, MITF and SOX10, regulate the emergence of distinct cell states associated with drug tolerance establishment after treatment.
“In melanoma, core regulators of neural crest lineage, MITF and SOX10, regulate the emergence of distinct cell states associated with drug tolerance establishment after treatment [61,82,83,84].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [83]
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The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data
McKenna, A., Hanna, M., Banks, E., Sivachenko, A., Cibulskis, K., Kernytsky, A., Garimella, K., Altshuler, D., Gabriel, S., Daly, M., et al. (2010) · Genome Research · doi:10.1101/gr.107524.110 · Cited by 27,895 · see citing works
A method and server for predicting damaging missense mutations.
Adzhubei, I. A., Schmidt, S., Peshkin, L., Ramensky, V. E., Gerasimova, A., Bork, P., Kondrashov, A. S., & Sunyaev, S. R. (2010) · Nature Methods · doi:10.1038/nmeth0410-248 · Cited by 13,194 · see citing works
Mutations of the BRAF gene in human cancer
Davies, H., Bignell, G. R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M. J., Bottomley, W., et al. (2002) · Nature · doi:10.1038/nature00766 · Cited by 10,674 · see citing works
Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing
Gerlinger, M., Rowan, A. J., Horswell, S., Larkin, J., Endesfelder, D., Gronroos, E., Martinez, P., Matthews, N., Stewart, A., Tarpey, P., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1113205 · Cited by 7,774 · see citing works
Improved survival with vemurafenib in melanoma with BRAF V600E mutation
Chapman, P. B., Hauschild, A., Robert, C., Haanen, J. B., Ascierto, P., Larkin, J., Dummer, R., Garbe, C., Testori, A., Maio, M., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1103782 · Cited by 7,720 · see citing works
Self-citationThe SWISS-MODEL workspace: a web-based environment for protein structure homology modelling
Arnold, K., Bordoli, L., Kopp, J., & Schwede, T. F. (2005) · Bioinformatics · doi:10.1093/bioinformatics/bti770 · Cited by 6,951 · see citing works
I-TASSER server for protein 3D structure prediction
Zhang, Y. (2008) · BMC Bioinformatics · doi:10.1186/1471-2105-9-40 · Cited by 5,124 · see citing works
Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples
Cibulskis, K., Lawrence, M. S., Carter, S. L., Sivachenko, A., Jaffe, D. B., Sougnez, C. L., Gabriel, S., Meyerson, M. M., Lander, E. S., & Getz, G. A. (2013) · Nature Biotechnology · doi:10.1038/nbt.2514 · Cited by 4,838 · see citing works
VarScan 2: Somatic mutation and copy number alteration discovery in cancer by exome sequencingPreprint
Koboldt, D. C., Zhang, Q., Larson, D. E., Shen, D., McLellan, M. D., Lin, L., Miller, C. A., Mardis, E. R., Ding, L., & Wilson, R. K. (2012) · Genome Research · doi:10.1101/gr.129684.111 · Cited by 4,822 · see citing works
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-citationHauschild, A., Grob, J., Демидов, Л. В., Jouary, T., Gutzmer, R., Millward, M. J., Rutkowski, P. L., Blank, C. U., Miller, W. H., Kaempgen, E., et al. (2012) · The Lancet · doi:10.1016/s0140-6736(12)60868-x · Cited by 2,975 · see citing works
Combined 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-citationA landscape of driver mutations in melanoma
Hodis, E., Watson, I. R., Kryukov, G. V., Arold, S. T., Imielinski, M., Theurillat, J.-P., Nickerson, E., Auclair, D., Li, L., Place, C., et al. (2012) · Cell · doi:10.1016/j.cell.2012.06.024 · Cited by 2,610 · see citing works
Detection of nonneutral substitution rates on mammalian phylogenies
Pollard, K. S., Hubisz, M. J., Rosenbloom, K. R., & Siepel, A. (2010) · Genome Research · doi:10.1101/gr.097857.109 · Cited by 2,353 · see citing works
COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer
Forbes, S. A., Bindal, N., Bamford, S., Cole, C., Kok, C. Y., Beare, D., Jia, M., Shepherd, R., Leung, K., Menzies, A., et al. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkq929 · Cited by 2,278 · see citing works
Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis
DeNicola, G. M., Karreth, F. A., Humpton, T. J., Gopinathan, A., Wei, C., Frese, K., Mangal, D., Yu, K. H., Yeo, C. J., Calhoun, E. S., et al. (2011) · Nature · doi:10.1038/nature10189 · Cited by 2,277 · see citing works
Melanomas 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-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-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-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-citationNon-invasive analysis of acquired resistance to cancer therapy by sequencing of plasma DNA
Murtaza, M., Dawson, S.-J., Tsui, D. W. Y., Gale, D., Forshew, T., Piskorz, A. M., Parkinson, C., Chin, S.-F., Kingsbury, Z., Wong, A. S. C., et al. (2013) · Nature · doi:10.1038/nature12065 · Cited by 1,624 · 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
RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E)
Poulikakos, P. I., Persaud, Y., Janakiraman, M., Kong, X., Ng, C., Moriceau, G., Shi, H., Atefi, M., Titz, B., Gabay, M. T., et al. (2011) · Nature · doi:10.1038/nature10662 · Cited by 1,454 · 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-citationNon-Invasive Analysis of Acquired Resistance to Cancer Therapy By Sequencing of Plasma Dna
(2014) · Annals of Oncology · doi:10.1093/annonc/mdu312.5 · Cited by 1,174 · see citing works
Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors
Wilson, T. R., Fridlyand, J., Yan, Y., Penuel, E., Burton, L., Chan, E., Peng, J., Lin, E., Wang, Y., Sosman, J., et al. (2012) · Nature · doi:10.1038/nature11249 · Cited by 1,134 · see citing works
Lee, J.-O., Yang, H.-J., Georgescu, M., Cristofano, A. D., Maehama, T., Shi, Y., Dixon, J., Pandolfi, P., & Pavletich, N. (1999) · Cell · doi:10.1016/s0092-8674(00)81663-3 · Cited by 1,096 · see citing works
Stephens, L., Anderson, K. E., Stokoe, D., Erdjument‐Bromage, H., Painter, G. F., Holmes, A. B., Gaffney, P. R. J., Reese, C. B., McCormick, F. P., Tempst, P., et al. (1998) · Science · doi:10.1126/science.279.5351.710 · Cited by 1,061 · 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
Plagnol, V., Curtis, J. W., Epstein, M., Mok, K. Y., Stebbings, E., Grigoriadou, S., Wood, N. W., Hambleton, S., Burns, S. O., Thrasher, A. J., et al. (2012) · Bioinformatics · doi:10.1093/bioinformatics/bts526 · Cited by 738 · see citing works
Chromatin organization is a major influence on regional mutation rates in human cancer cells
Schuster-Böckler, B., & Lehner, B. (2012) · Nature · doi:10.1038/nature11273 · Cited by 657 · see citing works
Shi, H., Moriceau, G., Kong, X., Lee, M., Lee, H., Koya, R. C., Ng, C., Chodon, T., Scolyer, R. A., Dahlman, K. B., et al. (2012) · Nature Communications · doi:10.1038/ncomms1727 · Cited by 637 · see citing works
Self-citationParaiso, K. H. T., Xiang, Y., Rebecca, V. W., Abel, E. V., Chen, Y. A., Munko, A. C., Wood, E. R., Smalley, I., Sondak, V. K., Anderson, A. R. A., et al. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-2954 · Cited by 551 · see citing works
Self-citationCheung, L. W. T., Hennessy, B. T., Li, J., Yu, S., Myers, A. P., Djordjevic, B., Lu, Y., Stemke‐Hale, K., Dyer, M. D., Zhang, F., et al. (2011) · Cancer Discovery · doi:10.1158/2159-8290.cd-11-0039 · Cited by 469 · see citing works
Girotti, M. R., Pedersen, M., Sánchez‐Laorden, B. L., Virós, A., Turajlic, S., Niculescu‐Duvaz, D., Zambon, A., Sinclair, J., Hayes, A. J., Gore, M. E., et al. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0386 · Cited by 380 · see citing works
Exome sequencing-based copy-number variation and loss of heterozygosity detection: ExomeCNV
Sathirapongsasuti, J. F., Lee, H., Horst, B. A. J., Brunner, G., Cochran, A. J., Binder, S. W., Quackenbush, J. F., & Nelson, S. F. (2011) · Bioinformatics · doi:10.1093/bioinformatics/btr462 · Cited by 374 · see citing works
Trunzer, K., Pavlick, A. C., Schuchter, L. M., Gonzalez, R. C., McArthur, G. A., Hutson, T. E., Moschos, S. J., Flaherty, K. T., Kim, K. B., Weber, J. S., et al. (2013) · Journal of Clinical Oncology · doi:10.1200/jco.2012.44.7888 · Cited by 366 · see citing works
Self-citationThe Implications of Clonal Genome Evolution for Cancer Medicine
Aparicio, S. A. J. R., & Caldas, C. (2013) · New England Journal of Medicine · doi:10.1056/nejmra1204892 · Cited by 350 · see citing works
Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E–mutated melanomas
Smalley, K. S. M., Lioni, M., Palma, M. D., Xiao, M., Desai, B. M., Egyházi, S., Hansson, J., Wu, H., King, A. J., Belle, P. A. V., et al. (2008) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-08-0431 · Cited by 310 · see citing works
A frequent kinase domain mutation that changes the interaction between PI3Kα and the membrane
Mandelker, D. L., Gabelli, S. B., Schmidt‐Kittler, O., Zhu, J., Cheong, I., Huang, C., Kinzler, K. W., Vogelstein, B., & Amzel, L. M. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908444106 · Cited by 298 · see citing works
Milburn, C. C., Deák, M., Kelly, S. M., Price, N. C., Alessi, D. R., & van Aalten, D. M. F. (2003) · Biochemical Journal · doi:10.1042/bj20031229 · Cited by 262 · see citing works
Shi, H., Kong, X., Ribas, A., & Lo, R. S. (2011) · Cancer Research · doi:10.1158/0008-5472.can-11-0140 · Cited by 222 · see citing works
Self-citationMarks, J. L., Gong, Y., Chitale, D. A., Golas, B., McLellan, M. D., Kasai, Y., Ding, L., Mardis, E. R., Wilson, R. K., Solit, D. B., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-0099 · Cited by 213 · see citing works
Hou, S., Zhao, L., Shen, Q., Yu, J., Ng, C., Kong, X., Wu, D., Song, M., Shi, X., Xu, X., et al. (2013) · Angewandte Chemie International Edition · doi:10.1002/anie.201208452 · Cited by 212 · see citing works
Self-citationA Novel AKT1 Mutant Amplifies an Adaptive Melanoma Response to BRAF Inhibition
Shi, H., Hong, A., Kong, X., Koya, R. C., Song, C., Moriceau, G., Hugo, W., Yu, C. C., Ng, C., Chodon, T., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0279 · Cited by 174 · see citing works
Self-citationCytosine Methylation and DNA Repair
Walsh, C. P., & Xu, G. L. (2006) · Springer eBooks · doi:10.1007/3-540-31390-7_11 · Cited by 139 · see citing works
Suppression of survival signalling pathways by the phosphatase PHLPP
O’Neill, A., Niederst, M. J., & Newton, A. C. (2012) · FEBS Journal · doi:10.1111/j.1742-4658.2012.08537.x · Cited by 107 · see citing works
Shi, H., Moriceau, G., Kong, X., Koya, R. C., Nazarian, R., Pupo, G. M., Bacchiocchi, A., Dahlman, K. B., Chmielowski, B., Sosman, J. A., et al. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0022 · Cited by 99 · see citing works
Self-citationTHOMAS, C. C., DOWLER, S., Deák, M., Alessi, D. R., & van Aalten, D. M. F. (2001) · Biochemical Journal · doi:10.1042/0264-6021:3580287 · Cited by 98 · see citing works
The BRAFV600E causes widespread alterations in gene methylation in the genome of melanoma cells
Hou, P., Liu, D., Dong, J., & Xing, M. (2012) · Cell Cycle · doi:10.4161/cc.11.2.18707 · Cited by 91 · see citing works
THOMAS, C. C., DOWLER, S., Deák, M., et al. (2001) · Biochemical Journal · doi:10.1042/bj3580287 · Cited by 72 · see citing works
Meeting report from the S ociety for M elanoma R esearch 2012 C ongress, H ollywood, C alifornia
Lo, R. S., Ribas, A., Long, G., et al. (2013) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12103 · Cited by 4 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma
Hugo, W., Zaretsky, J. M., Sun, L., Song, C., Moreno, B. H., Hu-Lieskovan, S., Berent-Maoz, B., Pang, J., Chmielowski, B., Cherry, G., et al. (2016) · Cell · doi:10.1016/j.cell.2016.02.065 · Cited by 3,448 · see citing works
Self-citationMutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma
Zaretsky, J. M., Garcia-Diaz, A., Shin, D. S., Escuin-Ordinas, H., Hugo, W., Hu-Lieskovan, S., Torrejon, D. Y., Abril-Rodriguez, G., Sandoval, S., Barthly, L., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1604958 · Cited by 3,237 · see citing works
Self-citationClonal heterogeneity and tumor evolution: past, present, and the future
McGranahan, N., & Swanton, C. (2017) · Cell · doi:10.1016/j.cell.2017.01.018 · Cited by 2,840 · see citing works
Gao, H., Korn, J. M., Ferretti, S., Monahan, J. E., Wang, Y., Singh, M., Zhang, C., Schnell, C., Yang, G., Zhang, Y., et al. (2015) · Nature Medicine · doi:10.1038/nm.3954 · Cited by 1,393 · see citing works
Primary Resistance to PD-1 Blockade Mediated by <i>JAK1/2</i> Mutations
Shin, D. S., Zaretsky, J. M., Escuin-Ordinas, H., Garcia-Diaz, A., Hu-Lieskovan, S., Kalbasi, A., Grasso, C. S., Hugo, W., Sandoval, S., Torrejon, D. Y., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-1223 · Cited by 1,337 · see citing works
Self-citationA dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells
Carreno, B. M., Magrini, V., Becker-Hapak, M., Kaabinejadian, S., Hundal, J., Petti, A. A., Ly, A., Lie, W.-R., Hildebrand, W. H., Mardis, E. R., et al. (2015) · Science · doi:10.1126/science.aaa3828 · Cited by 1,285 · see citing works
Targeting 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
Biological and therapeutic impact of intratumor heterogeneity in cancer evolution
McGranahan, N., & Swanton, C. (2015) · Cancer Cell · doi:10.1016/j.ccell.2014.12.001 · Cited by 1,077 · see citing works
Spatial and temporal diversity in genomic instability processes defines lung cancer evolution
de Bruin, E. C., McGranahan, N., Mitter, R., Salm, M., Wedge, D. C., Yates, L., Jamal-Hanjani, M., Shafi, S., Murugaesu, N., Rowan, A. J., et al. (2014) · Science · doi:10.1126/science.1253462 · Cited by 1,117 · see citing works
Overcoming Endocrine Resistance in Breast Cancer
Hanker, A. B., Sudhan, D. R., & Arteaga, C. L. (2020) · Cancer Cell · doi:10.1016/j.ccell.2020.03.009 · Cited by 927 · 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
Xenograft and organoid model systems in cancer research
Bleijs, M., van de Wetering, M., Clevers, H., & Drost, J. (2019) · The EMBO Journal · doi:10.15252/embj.2019101654 · Cited by 400 · 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
Combine and conquer: challenges for targeted therapy combinations in early phase trials
Lopez, J. S., & Banerji, U. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.96 · Cited by 394 · see citing works
Long, 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
Self-citationOvercoming resistance to tumor-targeted and immune-targeted therapies
Aldea, M., Andre, F., Marabelle, A., Dogan, S., Barlesi, F., & Soria, J.-C. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-1638 · Cited by 311 · see citing works
Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy
Eroglu, Z., & Ribas, A. (2016) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758834015616934 · Cited by 316 · see citing works
Self-citationAmaria, R. N., Prieto, P. A., Tetzlaff, M. T., Reuben, A., Andrews, M. C., Ross, M. I., Glitza, I. C., Cormier, J., Hwu, W.-J., Tawbi, H. A., et al. (2018) · The Lancet Oncology · doi:10.1016/s1470-2045(18)30015-9 · Cited by 299 · 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
Boshuizen, J., Koopman, L. A., Krijgsman, O., Shahrabi, A., van den Heuvel, E. G., Ligtenberg, M. A., Vredevoogd, D. W., Kemper, K., Kuilman, T., Song, J.-Y., et al. (2018) · Nature Medicine · doi:10.1038/nm.4472 · Cited by 229 · see citing works
Phenotype Switching: Tumor Cell Plasticity as a Resistance Mechanism and Target for Therapy
Kemper, K., de Goeje, P. L., Peeper, D. S., & van Amerongen, R. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-1174 · Cited by 216 · 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
Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer
Cabanos, H. F., & Hata, A. N. (2021) · Cancers · doi:10.3390/cancers13112666 · Cited by 189 · see citing works
Genomic and immune heterogeneity are associated with differential responses to therapy in melanoma
Reuben, A., Spencer, C. N., Prieto, P. A., Gopalakrishnan, V., Reddy, S. M., Miller, J. P., Mao, X., De Macedo, M. P., Chen, J., Song, X., et al. (2017) · npj Genomic Medicine · doi:10.1038/s41525-017-0013-8 · Cited by 166 · see citing works
Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors
Mulcahy Levy, J. M., Zahedi, S., Griesinger, A. M., Morin, A., Davies, K. D., Aisner, D. L., Kleinschmidt-DeMasters, B., Fitzwalter, B. E., Goodall, M. L., Thorburn, J., et al. (2017) · eLife · doi:10.7554/elife.19671 · 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
Trujillo, J. A., Luke, J. J., Zha, Y., Segal, J. P., Ritterhouse, L. L., Spranger, S., Matijevich, K., & Gajewski, T. F. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0780-0 · Cited by 159 · 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
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
Vemurafenib resistance reprograms melanoma cells towards glutamine dependence
Hernandez-Davies, J. E., Tran, T. Q., Reid, M. A., Rosales, K. R., Lowman, X. H., Pan, M., Moriceau, G., Yang, Y., Wu, J., Lo, R. S., et al. (2015) · Journal of Translational Medicine · doi:10.1186/s12967-015-0581-2 · Cited by 131 · see citing works
Self-citationCombination 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
Circulating tumour DNA (CtDNA) as a liquid biopsy for melanoma
Calapre, L., Warburton, L., Millward, M., Ziman, M., & Gray, E. S. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.06.030 · Cited by 118 · 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
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
Brufsky, A., Kim, S. B., Zvirbule, Ž., Eniu, A., Mebis, J., Sohn, J. H., Wongchenko, M., Chohan, S., Amin, R., Yan, Y., et al. (2021) · Annals of Oncology · doi:10.1016/j.annonc.2021.01.065 · Cited by 92 · see citing works
The low affinity neurotrophin receptor CD271 regulates phenotype switching in melanoma
Restivo, G., Diener, J., Cheng, P. F., Kiowski, G., Bonalli, M., Biedermann, T., Reichmann, E., Levesque, M. P., Dummer, R., & Sommer, L. (2017) · Nature Communications · doi:10.1038/s41467-017-01573-6 · Cited by 82 · see citing works
HDAC8 regulates a stress response pathway in melanoma to mediate escape from BRAF inhibitor therapy
Emmons, M. F., Faião-Flores, F., Sharma, R., Thapa, R., Messina, J. L., Becker, J. C., Schadendorf, D., Seto, E., Sondak, V. K., Koomen, J. M., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-19-0040 · Cited by 73 · see citing works
Ahronian, L. G., & Corcoran, R. B. (2017) · Genome Medicine · doi:10.1186/s13073-017-0431-3 · Cited by 67 · see citing works
Protein–Protein Interactions: Emerging Oncotargets in the RAS-ERK Pathway
García-Gómez, R., Bustelo, X. R., & Crespo, P. (2018) · Trends in Cancer · doi:10.1016/j.trecan.2018.07.002 · Cited by 72 · see citing works
Wang, B., Zhang, W., Zhang, G., Kwong, L., Lu, H., Tan, J., Sadek, N., Xiao, M., Zhang, J., Labrie, M., et al. (2021) · Oncogene · doi:10.1038/s41388-021-01911-5 · Cited by 66 · 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
Kirouac, D. C., Schaefer, G., Chan, J., Merchant, M., Orr, C., Huang, S.-M. A., Moffat, J., Liu, L., Gadkar, K., & Ramanujan, S. (2017) · npj Systems Biology and Applications · doi:10.1038/s41540-017-0016-1 · Cited by 60 · see citing works
Giricz, O., Mo, Y., Dahlman, K. B., Cotto-Rios, X. M., Vardabasso, C., Nguyen, H., Matusow, B., Bartenstein, M., Polishchuk, V., Johnson, D. B., et al. (2018) · JCI Insight · doi:10.1172/jci.insight.120422 · Cited by 40 · see citing works
Self-citationDelgado-Goñi, T., Galobart, T. C., Wantuch, S., Normantaite, D., Leach, M. O., Whittaker, S. R., & Beloueche-Babari, M. (2020) · British Journal of Cancer · doi:10.1038/s41416-019-0628-x · Cited by 39 · see citing works
Yap1 Mediates Trametinib Resistance in Head and Neck Squamous Cell Carcinomas
Mudianto, T., Campbell, K. M., Webb, J., Zolkind, P., Skidmore, Z. L., Riley, R., Barnell, E. K., Ozgenc, I., Giri, T., Dunn, G. P., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-4179 · Cited by 33 · see citing works
Pearson, A. D., Gaspar, N., Janeway, K., Campbell-Hewson, Q., Lawlor, E. R., Copland, C., Karres, D., Norga, K., Benzaghou, F., Weiner, S., et al. (2022) · European Journal of Cancer · doi:10.1016/j.ejca.2022.06.008 · Cited by 22 · see citing works
Szadai, L., Velasquez, E., Szeitz, B., Almeida, N. P. D., Domont, G., Betancourt, L. H., Gil, J., Marko-Varga, M., Oskolas, H., Jánosi, Á. J., et al. (2021) · Cancers · doi:10.3390/cancers13236105 · Cited by 18 · see citing works
- Authors
- Shi, H., Hugo, W., Kong, X., Hong, A., Koya, R. C., Moriceau, G., Chodon, T., Guo, R., Johnson, D. B., Dahlman, K. B., Kelley, M. C., Kefford, R. F., Chmielowski, B., Glaspy, J. A., Sosman, J. A., van Baren, N., Long, G. V., Ribas, A., & Lo, R. S.
- Affiliations
- The University of Sydney (AU)
- Authors' Affiliations: 1Division of Dermatology, Department of Medicine, 2Division of Surgical Oncology, Department of Surgery, 3Division of Hematology & Oncology, Department of Medicine; 4Jonsson Comprehensive Cancer Center; 5Department of Molecular and Medical Pharmacology; 6David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California; Departments of 7Medicine, 8Cancer Biology, and 9Surgery, 10Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee; 11Melanoma Institute of Australia, Westmead Millennium Institute, Westmead Hospital, University of Sydney, Sydney, New South Wales, Australia; and 12Ludwig Institute for Cancer Research, Brussels Branch, Belgium
- Corresponding author
- Lo, Roger S.
- ORCID
- Venue
- Cancer Discovery
- Published
- 2014-01-01
- Volume
- 4
- Issue
- 1
- Pages
- 80-93
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC3936420
- OpenAlex
- W2105660237
- Cited by
- 982
- References
- 52
- Citations by year
- 2026: 22 · 2025: 30 · 2024: 56 · 2023: 64 · 2022: 62 · 2021: 75 · 2020: 96 · 2019: 83 · 2018: 108 · 2017: 122 · 2016: 96 · 2015: 84 · 2014: 79 · 2013: 2
- FWCI
- 38.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Digital Access to Libraries (submittedVersion)
- Funders
- American Skin Association
- Melanoma Research Alliance
- Sidney Kimmel Foundation for Cancer Research
- Vanderbilt University
- Cancer Institute NSW
- Plexxikon
- National Institutes of Health (UL1TR000124)
- Stand Up To Cancer (SU2C-AACR-IRG0409)
- Medical Research Council
- National Health and Medical Research Council
- National Cancer Institute (K22CA151638, K24CA097588, P01CA168585, K12CA090625, P30CA016042, R01CA176111)
- National Center for Advancing Translational Sciences
- Clinical and Translational Science Institute, University of California, Los Angeles (UL1TR000124)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- BRAF inhibitor resistance, BRAF V600-mutant melanoma, clonal evolution, tumor heterogeneity, MAPK pathway reactivation, RAS mutations, BRAF amplification, alternative splicing, PI3K/Akt signaling, mutational signatures, tumor fitness, disease progression, drug resistance mechanisms
- MeSH terms
- Vemurafenib, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Female, Humans, Imidazoles, Indoles, Male, Melanoma, Middle Aged, Oximes, Skin Neoplasms, Sulfonamides, ras Proteins, Drug Resistance, Neoplasm, Phosphatidylinositol 3-Kinases, Mitogen-Activated Protein Kinases, Cell Line, Tumor, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-akt, PTEN Phosphohydrolase, Clonal Evolution
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