The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
COT drives resistance to RAF inhibition through MAP kinase pathway reactivation
Open accessAbstract
Oncogenic mutations in the serine/threonine kinase B-RAF (also known as BRAF) are found in 50-70% of malignant melanomas. Pre-clinical studies have demonstrated that the B-RAF(V600E) mutation predicts a dependency on the mitogen-activated protein kinase (MAPK) signalling cascade in melanoma-an observation that has been validated by the success of RAF and MEK inhibitors in clinical trials. However, clinical responses to targeted anticancer therapeutics are frequently confounded by de novo or acquired resistance. Identification of resistance mechanisms in a manner that elucidates alternative 'druggable' targets may inform effective long-term treatment strategies. Here we expressed ∼600 kinase and kinase-related open reading frames (ORFs) in parallel to interrogate resistance to a selective RAF kinase inhibitor. We identified MAP3K8 (the gene encoding COT/Tpl2) as a MAPK pathway agonist that drives resistance to RAF inhibition in B-RAF(V600E) cell lines. COT activates ERK primarily through MEK-dependent mechanisms that do not require RAF signalling. Moreover, COT expression is associated with de novo resistance in B-RAF(V600E) cultured cell lines and acquired resistance in melanoma cells and tissue obtained from relapsing patients following treatment with MEK or RAF inhibitors. We further identify combinatorial MAPK pathway inhibition or targeting of COT kinase activity as possible therapeutic strategies for reducing MAPK pathway activation in this setting. Together, these results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies.
Overview
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
Verification
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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 [13]
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.
Citations
Cites
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
Self-citationMET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling
Engelman, J. A., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J. O., Lindeman, N., Gale, C.-M., Zhao, X., Christensen, J., et al. (2007) · Science · doi:10.1126/science.1141478 · Cited by 4,496
The landscape of somatic copy-number alteration across human cancers
Beroukhim, R., Mermel, C. H., Porter, D., Wei, G., Raychaudhuri, S., Donovan, J., Barretina, J., Boehm, J. S., Dobson, J., Urashima, M., et al. (2010) · Nature · doi:10.1038/nature08822 · Cited by 4,017
Self-citationSystematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1
Barbie, D. A., Tamayo, P., Boehm, J. S., Kim, S. Y., Moody, S. E., Dunn, I. F., Schinzel, A. C., Sandy, P., Meylan, E., Scholl, C., et al. (2009) · Nature · doi:10.1038/nature08460 · Cited by 3,922
Self-citationClinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification
Gorre, M. E., Mohammed, M., Ellwood, K., Hsu, N., Paquette, R., Rao, P. N., & Sawyers, C. L. (2001) · Science · doi:10.1126/science.1062538 · Cited by 3,104
Inhibition of Mutated, Activated BRAF in Metastatic Melanoma
Flaherty, K. T., Puzanov, I., Kim, K. B., Ribas, A., McArthur, G. A., Sosman, J. A., O'Dwyer, P. J., Lee, R. J., Grippo, J. F., Nolop, K., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1002011 · Cited by 3,103
Self-citationMechanism of Activation of the RAF-ERK Signaling Pathway by Oncogenic Mutations of B-RAF
Wan, P., Garnett, M. J., Roe, S. M., Lee, S., Niculescu‐Duvaz, D., Good, V. M., Cancer Genome Project, Jones, C. M., Marshall, C. J., Springer, C. J., et al. (2004) · Cell · doi:10.1016/s0092-8674(04)00215-6 · Cited by 2,863
RAF 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 1,841
RAF 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 1,649
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 1,497
Cited by
Sorted by citations
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
Self-citationOptimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9
Doench, J. G., Fusi, N., Sullender, M., Hegde, M., Vaimberg, E. W., Donovan, K. F., Smith, I., Tothova, Z., Wilen, C., Orchard, R., et al. (2016) · Nature Biotechnology · doi:10.1038/nbt.3437 · Cited by 4,637
Self-citationCancer drug resistance: an evolving paradigm
Holohan, C., Van Schaeybroeck, S., Longley, D. B., & Johnston, P. G. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3599 · Cited by 4,681
Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex
Konermann, S., Brigham, M. D., Trevino, A. E., Joung, J., Abudayyeh, O. O., Barcena, C., Hsu, P. D., Habib, N., Gootenberg, J. S., Nishimasu, H., et al. (2015) · Nature · doi:10.1038/nature14136 · Cited by 2,825
Hauschild, 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 3,050
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
Self-citationImproved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib
Robert, C., Karaszewska, B., Schachter, J., Rutkowski, P. L., Mackiewicz, A. A., Stroyakovskiy, D., Lichinitser, M., Dummer, R., Grange, F., Mortier, L., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1412690 · Cited by 2,763
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
Self-citationImproved Survival with MEK Inhibition in BRAF-Mutated Melanoma
Flaherty, K. T., Robert, C., Hersey, P., Nathan, P., Garbe, C., Milhem, M. M., Демидов, Л. В., Hassel, J. C., Rutkowski, P. L., Mohr, P., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1203421 · Cited by 2,205
Self-citationThe Ras-ERK and PI3K-mTOR pathways: cross-talk and compensation
Mendoza, M. C., Er, E. E., & Blenis, J. (2011) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2011.03.006 · Cited by 1,817
Liquid biopsy: monitoring cancer-genetics in the blood
Crowley, E. H., Nicolantonio, F. D., Loupakis, F., & Bardelli, A. (2013) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2013.110 · Cited by 1,857
Tumour 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
Self-citationThe molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers
Diaz Jr, L. A., Williams, R. T., Wu, J., Kinde, I., Hecht, J. R., Berlin, J., Allen, B., Bozic, I., Reiter, J. G., Nowak, M. A., et al. (2012) · Nature · doi:10.1038/nature11219 · Cited by 1,713
ERK1/2 MAP kinases: Structure, function, and regulation
Roskoski, R. J. (2012) · Pharmacological Research · doi:10.1016/j.phrs.2012.04.005 · Cited by 1,719
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
Self-citationLessons from the Cancer Genome
Garraway, L. A., & Lander, E. S. (2013) · Cell · doi:10.1016/j.cell.2013.03.002 · Cited by 1,377
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
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
Combinatorial 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
Optimized libraries for CRISPR-Cas9 genetic screens with multiple modalities
Sanson, K. R., Hanna, R. E., Hegde, M., Donovan, K. F., Strand, C., Sullender, M. E., Vaimberg, E. W., Goodale, A., Root, D. E., Piccioni, F., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-07901-8 · Cited by 1,043
Self-citationCancer Stem Cells: Impact, Heterogeneity, and Uncertainty
Magee, J. A., Piskounova, E., & Morrison, S. J. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.03.003 · Cited by 1,136
Ascierto, P. A., McArthur, G. A., Dréno, B., Atkinson, V. G., Liszkay, G., Giacomo, A. M. D., Mandalà, M., Демидов, Л. В., Stroyakovskiy, D., Thomas, L., et al. (2016) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30122-x · Cited by 1,041
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 1,028
Self-citationGlucocorticoid Receptor Confers Resistance to Antiandrogens by Bypassing Androgen Receptor Blockade
Arora, V. K., Schenkein, E., Murali, R., Subudhi, S. K., Wongvipat, J., Balbas, M., Shah, N., Cai, L., Efstathiou, E., Logothetis, C., et al. (2013) · Cell · doi:10.1016/j.cell.2013.11.012 · Cited by 1,013
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
Frederick, D. T., Piris, A., Cogdill, A. P., Cooper, Z. A., Lezcano, C., Ferrone, C. R., Mitra, D., Boni, A., Newton, L. P., Liu, C., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-1630 · Cited by 944
Self-citationFalchook, G. S., Long, G. V., Kurzrock, R., Kim, K. B., Arkenau, H., Brown, M. P., Hamid, O., Infante, J. R., Millward, M., Pavlick, A. C., et al. (2012) · The Lancet · doi:10.1016/s0140-6736(12)60398-5 · Cited by 954
The Genetic Landscape of Clinical Resistance to RAF Inhibition in Metastatic Melanoma
Allen, E. M. V., Wagle, N., Sucker, A., Treacy, D. J., Johannessen, C. M., Goetz, E. M., Place, C. S., Taylor-Weiner, A. N., Whittaker, S. R., Kryukov, G. V., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0617 · Cited by 921
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
Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies
Bahar, M. E., Kim, H. J., & Kim, D. R. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01705-z · Cited by 888
Quantitative Analysis of Hsp90-Client Interactions Reveals Principles of Substrate Recognition
Taipale, M., Krykbaeva, I., Koeva, M., Kayatekin, C., Westover, K. D., Karras, G. I., & Lindquist, S. (2012) · Cell · doi:10.1016/j.cell.2012.06.047 · Cited by 879
Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond
Holderfield, M. T., Deuker, M. M., McCormick, F. P., & McMahon, M. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3760 · Cited by 850
Targeting MAPK Signaling in Cancer: Mechanisms of Drug Resistance and Sensitivity
Lee, S., Rauch, J., & Kölch, W. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21031102 · Cited by 823
Allostery in Disease and in Drug Discovery
Nussinov, R., & Tsai, C. (2013) · Cell · doi:10.1016/j.cell.2013.03.034 · Cited by 769
Duncan, J. S., Whittle, M. C., Nakamura, K., Abell, A. N., Midland, A. A., Zawistowski, J. S., Johnson, N. L., Granger, D. A., Jordan, N. V., Darr, D. B., et al. (2012) · Cell · doi:10.1016/j.cell.2012.02.053 · Cited by 732
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
Self-citationRegulation of RAF protein kinases in ERK signalling
Lavoie, H., & Therrien, M. (2015) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3979 · Cited by 702
Exploring the Genomes of Cancer Cells: Progress and Promise
Stratton, M. R. (2011) · Science · doi:10.1126/science.1204040 · Cited by 711
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
Kinase fusions are frequent in Spitz tumours and spitzoid melanomas
Wiesner, T., He, J., Yelensky, R., Esteve‐Puig, R., Botton, T., Yeh, I., Lipson, D., Otto, G. A., Brennan, K. W., Murali, R., et al. (2014) · Nature Communications · doi:10.1038/ncomms4116 · Cited by 658
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 660
MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road
Caunt, C. J., Sale, M. J., Smith, P. D., & Cook, S. J. (2015) · Nature Reviews Cancer · doi:10.1038/nrc4000 · Cited by 606
Schadendorf, D., Fisher, D. E., Garbe, C., Gershenwald, J. E., Grob, J., Halpern, A. C., Herlyn, M., Marchetti, M. A., McArthur, G. A., Ribas, A., et al. (2015) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2015.3 · Cited by 628
Copper is required for oncogenic BRAF signalling and tumorigenesis
Brady, D. C., Crowe, M. S., Turski, M. L., Hobbs, G. A., Yao, X.-J., Chaikuad, A., Knapp, S., Xiao, K., Campbell, S. L., Thiele, D. J., et al. (2014) · Nature · doi:10.1038/nature13180 · Cited by 624
Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance
Hugo, W., Shi, H., Sun, L., Piva, M., Song, C., Kong, X., Moriceau, G., Hong, A., Dahlman, K. B., Johnson, D. B., et al. (2015) · Cell · doi:10.1016/j.cell.2015.07.061 · Cited by 618
Discovery of small molecule cancer drugs: Successes, challenges and opportunities
Hoelder, S., Clarke, P. A., & Workman, P. (2012) · Molecular Oncology · doi:10.1016/j.molonc.2012.02.004 · Cited by 591
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
A public genome-scale lentiviral expression library of human ORFs
Yang, X., Boehm, J. S., Yang, X., Salehi-Ashtiani, K., Hao, T., Shen, Y., Lubonja, R., Thomas, S. R., Alkan, O., Bhimdi, T., et al. (2011) · Nature Methods · doi:10.1038/nmeth.1638 · Cited by 570
Self-citationBRAF Inhibitor Resistance Mechanisms in Metastatic Melanoma: Spectrum and Clinical Impact
Rizos, H., Menzies, A. M., Pupo, G. M., Carlino, M. S., Fung, C., Hyman, J., Haydu, L. E., Mijatov, B., Becker, T. M., Boyd, S. C., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-3122 · Cited by 553
Katayama, R., Khan, T. M., Benes, C. H., Lifshits, E., Ebi, H., Rivera, V. M., Shakespeare, W. C., Iafrate, A. J., Engelman, J. A., & Shaw, A. T. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1019559108 · Cited by 553
A Melanoma Cell State Distinction Influences Sensitivity to MAPK Pathway Inhibitors
Konieczkowski, D. J., Johannessen, C. M., Abudayyeh, O. O., Kim, J. W., Cooper, Z. A., Piris, A., Frederick, D. T., Barzily-Rokni, M., Straussman, R., Haq, R., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0424 · Cited by 553
Self-citationSubbiah, V., Lassen, U., Élez, E., Italiano, A., Curigliano, G., Javle, M. M., de Braud, F., Prager, G. W., Greil, R., Stein, A., et al. (2020) · The Lancet Oncology · doi:10.1016/s1470-2045(20)30321-1 · Cited by 537
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
Self-citationMelanoma: 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
Self-citationJiang, 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
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
Self-citationKim, K. B., Kefford, R. F., Pavlick, A. C., Infante, J. R., Ribas, A., Sosman, J. A., Fecher, L. A., Millward, M., McArthur, G. A., Hwu, P., et al. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2012.43.5966 · Cited by 487
The 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
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
An overview of targeted cancer therapy
Padma, V. V. (2015) · Biomedicine · doi:10.7603/s40681-015-0019-4 · Cited by 500
Wei, G., Xi, W., Nussinov, R., & Ma, B. (2016) · Chemical Reviews · doi:10.1021/acs.chemrev.5b00562 · Cited by 436
A melanocyte lineage program confers resistance to MAP kinase pathway inhibition
Johannessen, C. M., Johnson, L. A., Piccioni, F., Townes, A., Frederick, D. T., Donahue, M. K., Narayan, R., Flaherty, K. T., Wargo, J. A., Root, D. E., et al. (2013) · Nature · doi:10.1038/nature12688 · Cited by 452
Self-citationMED12 Controls the Response to Multiple Cancer Drugs through Regulation of TGF-β Receptor Signaling
Huang, S., Hölzel, M., Knijnenburg, T., Schlicker, A., Roepman, P., McDermott, U., Garnett, M., Grernrum, W., Sun, C., Prahallad, A., et al. (2012) · Cell · doi:10.1016/j.cell.2012.10.035 · Cited by 430
Sullivan, R. J., Infante, J. R., Jankú, F., Wong, D. J. L., Sosman, J. A., Keedy, V. L., Patel, M. R., Shapiro, G. I., Mier, J. W., Tolcher, A. W., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-1119 · Cited by 446
Self-citationAdvances in sarcoma genomics and new therapeutic targets
Taylor, B. S., Barretina, J., Maki, R. G., Antonescu, C. R., Singer, S., & Ladanyi, M. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3087 · Cited by 444
Self-citationGenetic Interactions in Cancer Progression and Treatment
Ashworth, A., Lord, C. J., & Reis-Filho, J. S. (2011) · Cell · doi:10.1016/j.cell.2011.03.020 · Cited by 431
Therapeutic strategies to target RAS-mutant cancers
Ryan, M. B., & Corcoran, R. B. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-018-0105-0 · Cited by 420
Tumour heterogeneity and the evolution of polyclonal drug resistance
Burrell, R. A., & Swanton, C. (2014) · Molecular Oncology · doi:10.1016/j.molonc.2014.06.005 · Cited by 435
Yang, C., Li, Z., Bhatt, T., Dickler, M. N., Giri, D. D., Scaltriti, M., Baselga, J. M., Rosen, N. X., & Chandarlapaty, S. (2016) · Oncogene · doi:10.1038/onc.2016.379 · Cited by 420
Genetic Screens Identify Host Factors for SARS-CoV-2 and Common Cold Coronaviruses
Wang, R., Simoneau, C. R., Kulsuptrakul, J., Bouhaddou, M., Travisano, K. A., Hayashi, J. M., Carlson-Stevermer, J., Zengel, J. R., Richards, C. M., Fozouni, P., et al. (2020) · Cell · doi:10.1016/j.cell.2020.12.004 · Cited by 417
Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer
Formisano, L., Lu, Y., Servetto, A., Hanker, A. B., Jansen, V. M., Bauer, J. A., Sudhan, D. R., Zotano, Á. G., Croessmann, S., Guo, Y. P., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09068-2 · Cited by 416
Exome sequencing identifies recurrent mutations in NF1 and RASopathy genes in sun-exposed melanomas
Krauthammer, M. O., Kong, Y., Bacchiocchi, A., Evans, P., Pornputtapong, N., Wu, C., McCusker, J. P., Ma, S., Cheng, E., Straub, R., et al. (2015) · Nature Genetics · doi:10.1038/ng.3361 · Cited by 417
The clinical development of MEK inhibitors
Zhao, Y., & Adjei, A. A. (2014) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2014.83 · Cited by 410
Use of human embryonic stem cells to model pediatric gliomas with H3.3K27M histone mutation
Funato, K., Major, T., Lewis, P. W., Allis, C. D., & Tabar, V. (2014) · Science · doi:10.1126/science.1253799 · Cited by 390
Unravelling the complexity of metastasis — molecular understanding and targeted therapies
Sethi, N. S., & Kang, Y. (2011) · Nature reviews. Cancer · doi:10.1038/nrc3125 · Cited by 405
FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR
Bivona, T. G., Hieronymus, H., Parker, J., Chang, K., Taron, M., Rosell, R., Moonsamy, P., Dahlman, K., Miller, V. A., Costa, C., et al. (2011) · Nature · doi:10.1038/nature09870 · Cited by 396
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
Signal pathways of melanoma and targeted therapy
Guo, W., Wang, H., & Li, C. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00827-6 · Cited by 419
Oberholzer, P. A., Kee, D., Dziunycz, P., Sucker, A., Kamsu-Kom, N., Jones, R. T., Roden, C., Chalk, C. J., Ardlie, K., Palescandolo, E., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2011.36.7680 · Cited by 386
Self-citationInhibition of Ras for Cancer Treatment: The Search Continues
Baines, A. T., Xu, D., & Der, C. J. (2011) · Future Medicinal Chemistry · doi:10.4155/fmc.11.121 · Cited by 401
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 394
Liu, C., Peng, W., Xu, C., Lou, Y., Zhang, M., Wargo, J. A., Chen, J. Q., Li, H. S., Watowich, S. S., Yang, Y., et al. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-1626 · Cited by 386
Self-citationResistance to BRAF-targeted therapy in melanoma
Sullivan, R. J., & Flaherty, K. T. (2013) · European Journal of Cancer · doi:10.1016/j.ejca.2012.11.019 · Cited by 386
Self-citationCRISPRi and CRISPRa Screens in Mammalian Cells for Precision Biology and Medicine
Kampmann, M. (2017) · ACS Chemical Biology · doi:10.1021/acschembio.7b00657 · Cited by 387
Heterodimeric JAK–STAT activation as a mechanism of persistence to JAK2 inhibitor therapy
Koppikar, P., Bhagwat, N., Kilpivaara, O., Manshouri, T., Adli, M., Hricik, T., Liu, F., Saunders, L. M., Mullally, A., Abdel-Wahab, O. I., et al. (2012) · Nature · doi:10.1038/nature11303 · Cited by 374
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 378
Self-citationGreger, J., Eastman, S. D., Zhang, V., Bleam, M. R., Hughes, A. M., Smitheman, K. N., Dickerson, S. H., Laquerre, S. G., Liu, L., & Gilmer, T. M. (2012) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-11-0989 · Cited by 366
A Genome-Scale RNA Interference Screen Implicates NF1 Loss in Resistance to RAF Inhibition
Whittaker, S. R., Theurillat, J.-P. P., Allen, E. M. V., Wagle, N., Hsiao, J., Cowley, G. S., Schadendorf, D., Root, D. E., & Garraway, L. A. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0470 · Cited by 369
Self-citationNext-generation sequencing for cancer diagnostics: a practical perspective.
Meldrum, C. J., Doyle, M., & Tothill, R. W. (2011) · Europe PMC (PubMed Central) · Cited by 356
From genes to drugs: targeted strategies for melanoma
Flaherty, K. T., Hodi, F. S., & Fisher, D. E. (2012) · Nature reviews. Cancer · doi:10.1038/nrc3218 · Cited by 363
Self-citationMairet-Coello, G., Courchet, J., Pieraut, S., Courchet, V., Maximov, A., & Polleux, F. (2013) · Neuron · doi:10.1016/j.neuron.2013.02.003 · Cited by 351
Ten things you should know about protein kinases: IUPHAR R eview 14
Fabbro, D., Cowan‐Jacob, S. W., & Möbitz, H. (2015) · British Journal of Pharmacology · doi:10.1111/bph.13096 · Cited by 365
Effects of MAPK and PI3K Pathways on PD-L1 Expression in Melanoma
Atefi, M. S., Avramis, E. V., Lassen, A., Wong, D. J. L., Robert, L., Foulad, D. S., Cerniglia, M., Titz, B., Chodon, T., Graeber, T. G., et al. (2014) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-2797 · Cited by 344
Toward a Better Understanding of the Complexity of Cancer Drug Resistance
Gottesman, M. M., Lavi, O., Hall, M. D., & Gillet, J. (2015) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010715-103111 · Cited by 337
Johnson, D. B., Menzies, A. M., Zimmer, L., Eroglu, Z., Ye, F., Zhao, S., Rizos, H., Sucker, A., Scolyer, R. A., Gutzmer, R., et al. (2015) · European Journal of Cancer · doi:10.1016/j.ejca.2015.08.022 · Cited by 331
Self-citationTherapeutic Strategies for Targeting Ras Proteins
Gysin, S., Salt, M. B., Young, A. E., & McCormick, F. (2011) · Genes & Cancer · doi:10.1177/1947601911412376 · Cited by 329
McCubrey, J. A., Steelman, L. S., Chappell, W. H., Abrams, S. L., Franklin, R. A., Montalto, G., Cervello, M., Libra, M., Candido, S., Malaponte, G., et al. (2012) · Oncotarget · doi:10.18632/oncotarget.659 · Cited by 317
Challenges for assessing replicability in preclinical cancer biology
Errington, T. M., Denis, A., Perfito, N., Iorns, E., & Nosek, B. A. (2021) · eLife · doi:10.7554/elife.67995 · Cited by 345
Epigenetic mechanisms in tumorigenesis, tumor cell heterogeneity and drug resistance
Wilting, R. H., & Dannenberg, J. (2012) · Drug Resistance Updates · doi:10.1016/j.drup.2012.01.008 · Cited by 309
Mao, M., Tian, F., Mariadason, J. M., Tsao, C. C., Lemos, R., Dayyani, F., Gopal, Y. N. V., Jiang, Z.-Q., Wistuba, I. I., Tang, X. M., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-1446 · Cited by 290
Metadata
- Authors
- 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., Caponigro, G., Hieronymus, H., Murray, R. R., Salehi-Ashtiani, K., Hill, D. E., Vidal, M., Zhao, J. J., Yang, X., Alkan, O., Kim, S., Harris, J. L., Wilson, C. J., Myer, V. E., Finan, P. M., Root, D. E., Roberts, T. M., Golub, T., Flaherty, K. T., Dummer, R., Weber, B. L., Sellers, W. R., Schlegel, R., Wargo, J. A., Hahn, W. C., & Garraway, L. A.
- Affiliations
- Broad Institute (US)
- Harvard University (US)
- Massachusetts General Hospital (US)
- Genomics Institute of the Novartis Research Foundation (US)
- Dana-Farber Cancer Institute (US)
- University of Zurich (CH)
- Corresponding author
- Garraway, Levi A.
- ORCID
- Johannessen, Cory M.
- Boehm, Jesse S.
- Kim, So Young
- Stransky, Nicolas
- Cogdill, Alexandria P.
- Barretina, Jordi
- Hill, David E.
- Vidal, Marc
- Zhao, Jean J.
- Yang, Xiaoping
- Alkan, Ozan
- Wilson, Christopher J.
- Myer, Vic E.
- Root, David E.
- Roberts, Thomas M.
- Golub, Todd
- Flaherty, Keith T.
- Dummer, Reinhard
- Weber, Barbara L.
- Sellers, William R.
- Wargo, Jennifer A.
- Hahn, William C.
- Garraway, Levi A.
- Venue
- Nature
- Published
- 2010-11-24
- Volume
- 468
- Issue
- 7326
- Pages
- 968-972
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3058384
- OpenAlex
- W2141674733
- Cited by
- 1,460
- References
- 30
- Citations by year
- 2026: 19 · 2025: 27 · 2024: 32 · 2023: 55 · 2022: 45 · 2021: 56 · 2020: 67 · 2019: 91 · 2018: 78 · 2017: 102 · 2016: 107 · 2015: 121 · 2014: 158 · 2013: 186 · 2012: 177
- FWCI
- 65.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Funders
- National Institutes of Health (DP2OD002750)
- National Cancer Institute (RC2CA148268, R01CA134502, K08CA115927, CA134502, R33CA128625, P50CA093683)
- 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
- MAP3K8, BRAF inhibitor resistance, vemurafenib, melanoma, BRAF V600E mutation, MAPK signaling
- MeSH terms
- Vemurafenib, Allosteric Regulation, Clinical Trials as Topic, Enzyme Activation, Humans, Indoles, Melanoma, Proto-Oncogene Proteins, Sulfonamides, Gene Library, Gene Expression Regulation, Neoplastic, Open Reading Frames, Drug Resistance, Neoplasm, Proto-Oncogene Proteins c-raf, Gene Expression Profiling, Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase Kinases, MAP Kinase Kinase Kinases, MAP Kinase Signaling System, Cell Line, Tumor, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf
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
