Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion
Open accessAbstract
Drug resistance presents a challenge to the treatment of cancer patients. Many studies have focused on cell-autonomous mechanisms of drug resistance. By contrast, we proposed that the tumour micro-environment confers innate resistance to therapy. Here we developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs. We found that stroma-mediated resistance is common, particularly to targeted agents. We characterized further the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibitors because most patients with this type of cancer show some degree of innate resistance. Proteomic analysis showed that stromal cell secretion of hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI(3)K)–AKT signalling pathways, and immediate resistance to RAF inhibition. Immunohistochemistry experiments confirmed stromal cell expression of HGF in patients with BRAF-mutant melanoma and showed a significant correlation between HGF expression by stromal cells and innate resistance to RAF inhibitor treatment. Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. More generally, this study indicates that the systematic dissection of interactions between tumours and their micro-environment can uncover important mechanisms underlying drug resistance.
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HGF has been implicated in mediating resistance to BRAF-targeted therapies by providing an alternative BRAF-independent mechanism for ERK-MAPK activation.
“In addition, HGF has been implicated in mediating resistance to BRAF-targeted therapies by providing an alternative BRAF-independent mechanism for ERK–MAPK activation113.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [113]
HGF-secreting fibroblasts rescued BRAF mutant melanoma cells from the BRAF inhibitor PLX4720.
“By screening cancer-fibroblast co-cultures with a panel of cytotoxic and targeted agents, Straussman et al. identified that HGF-secreting fibroblasts rescued BRAF mutant melanoma cells from the BRAF inhibitor PLX4720 [99].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [99]
The tumor microenvironment is a complex ecosystem comprised of multiple cell types that support the growth of tumor cells, facilitate tumor progression, and modulate therapeutic response to anti-cancer treatments.
“The tumor microenvironment is a complex ecosystem comprised of multiple cell types that support the growth of tumor cells, facilitate tumor progression, and modulate therapeutic response to anti-cancer treatments [29,99,100,120,121].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [99]
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Cites
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-citationKalluri, R., & Zeisberg, M. (2006) · Nature Reviews Cancer · doi:10.1038/nrc1877 · Cited by 4,538 · see citing works
<i>MET</i> 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 · see citing works
Microenvironmental regulation of metastasis
Joyce, J. A., & Pollard, J. W. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2618 · Cited by 3,684 · 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-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-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-citationUnresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR
Prahallad, A., Sun, C., Huang, S., Di Nicolantonio, F., Salazar, R., Zecchin, D., Beijersbergen, R. L., Bardelli, A., & Bernards, R. (2012) · Nature · doi:10.1038/nature10868 · Cited by 2,051 · see citing works
Clinical 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-citationCOT 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-citationRAF 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
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
Self-citationCorcoran, R. B., Ebi, H., Turke, A. B., Coffee, E. M., Nishino, M., Cogdill, A. P., Brown, R. D., Della Pelle, P., Dias-Santagata, D., Hung, K. E., et al. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-11-0341 · Cited by 1,022 · see citing works
Self-citationAspirin and the Risk of Colorectal Cancer in Relation to the Expression of COX-2
Chan, A. T., Ogino, S., & Fuchs, C. S. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa067208 · Cited by 776 · see citing works
Self-citationMulticomponent therapeutics for networked systems
Keith, C. T., Borisy, A. A., & Stockwell, B. R. (2005) · Nature Reviews Drug Discovery · doi:10.1038/nrd1609 · Cited by 769 · see citing works
Renzo, M. F. D., Olivero, M., Giacomini, A., Porte, H., Chastre, E., Mirossay, L., Nordlinger, B., Bretti, S., Bottardi, S., & Giordano, S. (1995) · PubMed · Cited by 456 · see citing works
Tumor Resistance to Alkylating Agents Conferred by Mechanisms Operative Only in Vivo
Teicher, B. A., Herman, T. S., Holden, S. A., Wang, Y., Pfeffer, M. R., Crawford, J. W., & Frei, E. (1990) · Science · doi:10.1126/science.2108497 · Cited by 327 · see citing works
Tumor resistance to alkylating agents conferred by mechanisms operative only in vivo
Teicher, B., Herman, T., Holden, S., Wang, Y., Pfeffer, M., Crawford, J., & Frei, E. (1990) · Science · doi:10.1126/science.247.4949.1457 · Cited by 327 · see citing works
McMillin, D. W., Delmore, J. E., Weisberg, E., Negri, J. M., Geer, D. C., Klippel, S., Mitsiades, N., Schlossman, R. L., Munshi, N. C., Kung, A. L., et al. (2010) · Nature Medicine · doi:10.1038/nm.2112 · Cited by 316 · see citing works
Wang, W., Li, Q., Yamada, T., Matsumoto, K., Matsumoto, I., Oda, M., Watanabe, G., Kayano, Y., Nishioka, Y., Sone, S., et al. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-1001 · Cited by 297 · see citing works
Du, J., Bernasconi, P., Clauser, K. R., Mani, D. R., Finn, S. P., Beroukhim, R., Burns, M., Julian, B., Peng, X. P., Hieronymus, H., et al. (2008) · Nature Biotechnology · doi:10.1038/nbt.1513 · Cited by 232 · see citing works
Self-citationAkt3-Mediated Resistance to Apoptosis in B-RAF–Targeted Melanoma Cells
Shao, Y., & Aplin, A. E. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-4471 · Cited by 194 · see citing works
Williams, R. T., Roussel, M. F., & Sherr, C. J. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0602030103 · Cited by 191 · see citing works
Kammula, U. S., Kuntz, E. J., Francone, T. D., Zeng, Z., Shia, J., Landmann, R., Paty, P. B., & Weiser, M. R. (2006) · Cancer Letters · doi:10.1016/j.canlet.2006.07.007 · Cited by 161 · see citing works
c-Met Is a Potentially New Therapeutic Target for Treatment of Human Melanoma
Puri, N., Ahmed, S., Janamanchi, V., Tretiakova, M., Zumba, O., Krausz, T. N., Jagadeeswaran, R., & Salgia, R. (2007) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-06-0776 · Cited by 155 · see citing works
Liu, C., Park, M., & Tsao, M. (1992) · PubMed · Cited by 142 · see citing works
Jiang, C. C., Lai, F., Thorne, R. F., Yang, F., Liu, H., Hersey, P., & Zhang, X. D. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2225 · Cited by 117 · see citing works
Direct Involvement of Breast Tumor Fibroblasts in the Modulation of Tamoxifen Sensitivity
Shekhar, M. P. V., Santner, S. J., Carolin, K. A., & Tait, L. R. (2007) · American Journal Of Pathology · doi:10.2353/ajpath.2007.061004 · Cited by 105 · see citing works
Wang, H., Daouti, S., Li, W., Yang, W., Rizzo, C., Higgins, B., Packman, K. E., Rosen, N. X., Boylan, J. F., Heimbrook, D. C., et al. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-4351 · Cited by 76 · see citing works
Expression of the c-Met Proteins in Malignant Skin Cancers
Lee, Y.-J., Kim, D., Lee, S.-H., Kim, D. W., Nam, H.-S., & Cho, M. K. (2011) · Annals of Dermatology · doi:10.5021/ad.2011.23.1.33 · Cited by 41 · see citing works
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Inferring tumour purity and stromal and immune cell admixture from expression data
Yoshihara, K., Shahmoradgoli, M., Martínez, E., Vegesna, R., Kim, H., Torres-Garcia, W., Treviño, V., Shen, H., Laird, P. W., Levine, D. A., et al. (2013) · Nature Communications · doi:10.1038/ncomms3612 · Cited by 9,778 · see citing works
Cancer 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 · see citing works
The biology and function of fibroblasts in cancer
Kalluri, R. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.73 · Cited by 4,366 · see citing works
A framework for advancing our understanding of cancer-associated fibroblasts
Sahai, E., Astsaturov, I., Cukierman, E., DeNardo, D. G., Egeblad, M., Evans, R. M., Fearon, D., Greten, F. R., Hingorani, S. R., Hunter, T., et al. (2020) · Nature Reviews Cancer · doi:10.1038/s41568-019-0238-1 · Cited by 3,863 · see citing works
Emerging Biological Principles of Metastasis
Lambert, A. W., Pattabiraman, D. R., & Weinberg, R. A. (2017) · Cell · doi:10.1016/j.cell.2016.11.037 · Cited by 3,075 · 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-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
Influence of tumour micro-environment heterogeneity on therapeutic response
Junttila, M. R., & de Sauvage, F. J. (2013) · Nature · doi:10.1038/nature12626 · Cited by 2,694 · see citing works
Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer
Öhlund, D., Handly-Santana, A., Biffi, G., Elyada, E., Almeida, A. S., Ponz-Sarvise, M., Corbo, V., Oni, T. E., Hearn, S. A., Lee, E. J., et al. (2017) · Journal of Experimental Medicine · doi:10.1084/jem.20162024 · Cited by 2,590 · see citing works
Drug resistance in cancer: An overview
Housman, G., Byler, S., Heerboth, S., Lapinska, K., Longacre, M., Snyder, N., & Sarkar, S. (2014) · Cancers · doi:10.3390/cancers6031769 · Cited by 2,463 · see citing works
Inflammation-induced cancer: Crosstalk between tumours, immune cells and microorganisms
Elinav, E., Nowarski, R., Thaiss, C. A., Hu, B., Jin, C., & Flavell, R. A. (2013) · Nature reviews. Cancer · doi:10.1038/nrc3611 · Cited by 2,000 · see citing works
Metastatic colonization by circulating tumour cells
Massagué, J., & Obenauf, A. C. (2016) · Nature · doi:10.1038/nature17038 · Cited by 2,062 · see citing works
Tumor microenvironment as a therapeutic target in cancer
Xiao, Y. Q., & Yu, D. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107753 · Cited by 1,977 · see citing works
Non-small-cell lung cancers: a heterogeneous set of diseases
Chen, Z., Brainson, C. F., Hammerman, P. S., Kim, C. F., & Wong, K. (2014) · Nature reviews. Cancer · doi:10.1038/nrc3775 · Cited by 1,935 · see citing works
Turning foes to friends: targeting cancer-associated fibroblasts
Chen, X., & Song, E. (2018) · Nature Reviews Drug Discovery · doi:10.1038/s41573-018-0004-1 · Cited by 1,884 · see citing works
Geller, L. T., Barzily-Rokni, M., Danino, T., Jonas, O. H., Shental, N., Nejman, D., Gavert, N., Zwang, Y., Cooper, Z. A., Shee, K., et al. (2017) · Science · doi:10.1126/science.aah5043 · Cited by 1,817 · see citing works
Self-citationTumor microenvironment and therapeutic response
Wu, T., & Dai, Y. (2017) · Cancer Letters · doi:10.1016/j.canlet.2016.01.043 · Cited by 1,802 · see citing works
Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer
Costa, A., Kieffer, Y., Scholer-Dahirel, A., Pelon, F., Bourachot, B., Cardon, M., Sirven, P., Magagna, I., Fuhrmann, L., Bernard, C., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.01.011 · Cited by 1,705 · see citing works
Biffi, G., Oni, T. E., Spielman, B., Hao, Y., Elyada, E., Park, Y., Preall, J., & Tuveson, D. A. (2019) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0710 · Cited by 1,360 · see citing works
Hepatocellular carcinoma: clinical frontiers and perspectives
Bruix, J., Gores, G. J., & Mazzaferro, V. (2014) · Gut · doi:10.1136/gutjnl-2013-306627 · Cited by 1,367 · see citing works
Ardito, F., Giuliani, M., PERRONE, D., Troiano, G., & Muzio, L. L. (2017) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2017.3036 · Cited by 1,349 · see citing works
Diversity and biology of cancer-associated fibroblasts
Biffi, G., & Tuveson, D. A. (2021) · Physiological Reviews · doi:10.1152/physrev.00048.2019 · Cited by 1,265 · see citing works
Lessons from the Cancer Genome
Garraway, L. A., & Lander, E. S. (2013) · Cell · doi:10.1016/j.cell.2013.03.002 · Cited by 1,322 · 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
Immunological hallmarks of stromal cells in the tumour microenvironment
Turley, S. J., Cremasco, V., & Astarita, J. L. (2015) · Nature Reviews Immunology · doi:10.1038/nri3902 · Cited by 1,140 · 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
Self-citationTargeting the tumour stroma to improve cancer therapy
Valkenburg, K. C., de Groot, A. E., & Pienta, K. J. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-018-0007-1 · Cited by 1,084 · see citing works
Sherman, M. H., Yu, R. T., Engle, D. D., Ding, N., Atkins, A. R., Tiriac, H., Collisson, E. A., Connor, F., Van Dyke, T., Kozlov, S., et al. (2014) · Cell · doi:10.1016/j.cell.2014.08.007 · Cited by 1,158 · see citing works
Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer
Dienstmann, R., Vermeulen, L., Guinney, J., Kopetz, S., Tejpar, S., & Tabernero, J. M. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2016.126 · Cited by 1,038 · see citing works
Glucocorticoid 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 985 · 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-citationCancer heterogeneity: implications for targeted therapeutics
Fisher, R. A., Pusztai, L., & Swanton, C. (2013) · British Journal of Cancer · doi:10.1038/bjc.2012.581 · Cited by 980 · see citing works
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 · see citing works
Fibroblast heterogeneity in the cancer wound
Öhlund, D., Elyada, E., & Tuveson, D. A. (2014) · The Journal of Experimental Medicine · doi:10.1084/jem.20140692 · Cited by 940 · see citing works
Discovering the anticancer potential of non-oncology drugs by systematic viability profiling
Corsello, S. M., Nagari, R. T., Spangler, R. D., Rossen, J., Kocak, M., Bryan, J. G., Humeidi, R., Peck, D., Wu, X., Tang, A. A., et al. (2020) · Nature Cancer · doi:10.1038/s43018-019-0018-6 · Cited by 878 · see citing works
Self-citationThe 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 904 · see citing works
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 · see citing works
Revisiting the hallmarks of cancer.
Fouad, Y. A., & Aanei, C. M. (2017) · Europe PMC (PubMed Central) · Cited by 873 · see citing works
Oncogenic BRAF Regulates Oxidative Metabolism via PGC1α and MITF
Haq, R., Shoag, J., Andreu-Perez, P., Yokoyama, S., Edelman, H., Rowe, G. C., Frederick, D. T., Hurley, A. D., Nellore, A., Kung, A. L., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.02.003 · Cited by 818 · see citing works
Self-citationBasu, A. B., Bodycombe, N. E., Cheah, J. H., Price, E. V., Liu, K., Schaefer, G. I., Ebright, R. Y., Stewart, M. L., Ito, D., Wang, S. Y., et al. (2013) · Cell · doi:10.1016/j.cell.2013.08.003 · Cited by 820 · see citing works
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 828 · see citing works
Vemurafenib: the first drug approved for BRAF-mutant cancer
Bollag, G. E., Tsai, J. Y., Zhang, J., Zhang, C., Ibrahim, P. N., Nolop, K. B., & Hirth, P. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3847 · Cited by 823 · see citing works
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Bardelli, A., Corso, S., Bertotti, A., Hobor, S., Valtorta, E., Siravegna, G., Sartore-Bianchi, A., Scala, E., Cassingena, A., Zecchin, D., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0558 · Cited by 657 · see citing works
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Evolutionary dynamics of cancer in response to targeted combination therapy
Božić, I., Reiter, J. G., Allen, B., Tibor Antal, A., Chatterjee, K., Shah, P., Moon, Y. S., Yaqubie, A., Kelly, N. E., Le, D. T., et al. (2013) · eLife · doi:10.7554/elife.00747 · Cited by 607 · 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
Emran, T. B., Shahriar, A., Mahmud, A. R., Rahman, T., Abir, M. H., Siddiquee, M. F. R., Ahmed, H., Rahman, N., Nainu, F., Wahyudin, E., et al. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.891652 · Cited by 606 · see citing works
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 604 · see citing works
Self-citationTumor 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-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
Stromal biology and therapy in pancreatic cancer: a changing paradigm
Neeße, A., Algül, H., Tuveson, D. A., & Gress, T. M. (2015) · Gut · doi:10.1136/gutjnl-2015-309304 · Cited by 562 · see citing works
Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells
Lee, H.-J., Zhuang, G., Cao, Y., Du, P., Kim, H.-J., & Settleman, J. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.05.019 · Cited by 555 · see citing works
Eggermont, A. M. M., Spatz, A., & Robert, C. (2013) · The Lancet · doi:10.1016/s0140-6736(13)60802-8 · Cited by 560 · see citing works
BRAF 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 543 · see citing works
The obese adipose tissue microenvironment in cancer development and progression
Quail, D. F., & Dannenberg, A. J. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0126-x · Cited by 542 · see citing works
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 526 · see citing works
Self-citationThe present and future of the Cancer Dependency Map
Arafeh, R., Shibue, T., Dempster, J. M., Hahn, W. C., & Vazquez, F. (2025) · Nature Reviews Cancer · doi:10.1038/s41568-024-00763-x · Cited by 454 · see citing works
Glioblastoma: From Molecular Pathology to Targeted Treatment
Cloughesy, T. F., Cavenee, W. K., & Mischel, P. S. (2011) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-011110-130324 · Cited by 513 · see citing works
Tyrosine Kinase Inhibitors in Cancer: Breakthrough and Challenges of Targeted Therapy
Pottier, C., Fresnais, M., Gilon, M., Jérusalem, G., Longuespée, R., & Sounni, N. E. (2020) · Cancers · doi:10.3390/cancers12030731 · Cited by 516 · see citing works
Rational combinations of targeted cancer therapies: background, advances and challenges
Jin, H., Wang, L., & Bernards, R. (2023) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00615-z · Cited by 503 · see citing works
A RASopathy gene commonly mutated in cancer: the neurofibromatosis type 1 tumour suppressor
Ratner, N., & Miller, S. J. (2015) · Nature reviews. Cancer · doi:10.1038/nrc3911 · Cited by 488 · see citing works
Therapy-induced tumour secretomes promote resistance and tumour progression
Obenauf, A. C., Zou, Y., Ji, A. L., Vanharanta, S., Shu, W., Shi, H., Kong, X., Bosenberg, M., Wiesner, T., Rosen, N. X., et al. (2015) · Nature · doi:10.1038/nature14336 · Cited by 485 · see citing works
Self-citation3D cell culture systems modeling tumor growth determinants in cancer target discovery
Thoma, C. R., Zimmermann, M., Agarkova, I., Kelm, J. M., & Krek, W. (2014) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2014.03.001 · Cited by 478 · see citing works
Fibroblasts in cancer: Unity in heterogeneity
Chhabra, Y., & Weeraratna, A. T. (2023) · Cell · doi:10.1016/j.cell.2023.03.016 · Cited by 488 · see citing works
Wagle, 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
Lucas, J. M., Heinlein, C. A., Kim, T., Hernández, S., Malik, M. S., True, L. D., Morrissey, C. M., Corey, E., Montgomery, B., Mostaghel, E. A., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-1010 · Cited by 468 · 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
Quan, T., & Fisher, G. J. (2015) · Gerontology · doi:10.1159/000371708 · Cited by 464 · see citing works
Cancer-Associated Fibroblasts Build and Secure the Tumor Microenvironment
Liu, T., Zhou, L., Li, D., Andl, T., & Zhang, Y. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00060 · Cited by 446 · see citing works
Tumour-associated mesenchymal stem/stromal cells: emerging therapeutic targets
Shi, Y.-F., Du, L., Lin, L.-Y., & Wang, Y. (2016) · Nature reviews. Drug discovery · doi:10.1038/nrd.2016.193 · Cited by 409 · see citing works
m6A modification controls the innate immune response to infection by targeting type I interferons
Winkler, R., Gillis, E., Lasman, L., Safra, M., Geula, S., Soyris, C., Nachshon, A., Tai-Schmiedel, J., Friedman, N., Le‐Trilling, V. T. K., et al. (2018) · Nature Immunology · doi:10.1038/s41590-018-0275-z · Cited by 454 · see citing works
Cancer stem cells and chemoresistance: The smartest survives the raid
Zhao, J. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.02.008 · Cited by 433 · see citing works
Cazet, A. S., Hui, M. N., Elsworth, B. L., Wu, S. Z., Roden, D., Chan, C.-L., Skhinas, J. N., Collot, R., Yang, J., Harvey, K., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05220-6 · Cited by 437 · see citing works
Ishii, G., Ochiai, A., & Neri, S. (2015) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2015.07.007 · Cited by 431 · see citing works
Qin, X., Guo, H.-Y., Wang, X.-N., Zhu, X.-Q., Yan, M., Wang, X., Xu, Q., Shi, J.-B., Lu, E., Chen, W., et al. (2019) · Genome Biology · doi:10.1186/s13059-018-1604-0 · Cited by 386 · see citing works
Martinez-Outschoorn, U. E., Lisanti, M. P., & Sotgia, F. (2014) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2014.01.005 · Cited by 423 · 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
Effector T Cells Abrogate Stroma-Mediated Chemoresistance in Ovarian Cancer
Wang, W., Kryczek, I., Dostál, L., Lin, H., Tan, L., Zhao, L., Lu, F., Wei, S., Maj, T., Peng, D., et al. (2016) · Cell · doi:10.1016/j.cell.2016.04.009 · Cited by 423 · see citing works
Tumor Microenvironment and Differential Responses to Therapy
Hirata, E., & Sahai, E. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a026781 · Cited by 422 · see citing works
Evolutionary Determinants of Cancer
Greaves, M. F. (2015) · Cancer Discovery · doi:10.1158/2159-8290.cd-15-0439 · Cited by 411 · see citing works
Dieci, M., Arnedos, M., André, F., & Soria, J. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0362 · Cited by 393 · see citing works
Molecular aspects of cancer cell resistance to chemotherapy
Rebucci, M., & Michiels, C. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2013.02.017 · Cited by 409 · see citing works
The folate receptor as a rational therapeutic target for personalized cancer treatment
Assaraf, Y. G., Leamon, C. P., & Reddy, J. A. (2014) · Drug Resistance Updates · doi:10.1016/j.drup.2014.10.002 · Cited by 399 · see citing works
Montero-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
The Reprogramming of Tumor Stroma by HSF1 Is a Potent Enabler of Malignancy
Scherz-Shouval, R., Santagata, S., Mendillo, M. L., Sholl, L. M., Ben-Aharon, I., Beck, A. H., Dias-Santagata, D., Koeva, M., Stemmer, S. M., Whitesell, L., et al. (2014) · Cell · doi:10.1016/j.cell.2014.05.045 · Cited by 386 · 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
Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy
Comoglio, P. M., Trusolino, L., & Boccaccio, C. (2018) · Nature reviews. Cancer · doi:10.1038/s41568-018-0002-y · Cited by 380 · see citing works
Hickman, J. A., Graeser, R., Hoogt, R. D., Vidic, S., Brito, C., Gutekunst, M., & van der Kuip, H. (2014) · Biotechnology Journal · doi:10.1002/biot.201300492 · Cited by 379 · see citing works
Therapy resistance: opportunities created by adaptive responses to targeted therapies in cancer
Labrie, M., Brugge, J. S., Mills, G. B., & Zervantonakis, I. K. (2022) · Nature reviews. Cancer · doi:10.1038/s41568-022-00454-5 · Cited by 388 · see citing works
Resistance 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 373 · see citing works
Self-citation‘Cancer associated fibroblasts’ – more than meets the eye
Madar, S., Goldstein, I., & Rotter, V. (2013) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2013.05.004 · Cited by 362 · see citing works
Lotti, F., Jarrar, A., Pai, R. K., Hitomi, M., Lathia, J. D., Mace, A. G., Gantt, G., Sukhdeo, K., DeVecchio, J., Vasanji, A., et al. (2013) · The Journal of Experimental Medicine · doi:10.1084/jem.20131195 · Cited by 362 · see citing works
- Authors
- Straussman, R., Morikawa, T., Shee, K., Barzily-Rokni, M., Qian, Z. R., Du, J., Davis, A., Mongare, M. M., Gould, J., Frederick, D. T., Cooper, Z. A., Chapman, P. B., Solit, D. B., Ribas, A., Lo, R. S., Flaherty, K. T., Ogino, S., Wargo, J. A., & Golub, T. R.
- Affiliations
- Broad Institute (US)
- Dana-Farber Cancer Institute (US)
- Massachusetts General Hospital (US)
- Memorial Sloan Kettering Cancer Center (US)
- University of California, Los Angeles (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Golub, Todd R.
- ORCID
- Venue
- Nature
- Published
- 2012-07
- Volume
- 487
- Issue
- 7408
- Pages
- 500-504
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3711467
- OpenAlex
- W2055624262
- Semantic Scholar
- d51bc0a1730710ad5e74705bff1a2f756c61fc28
- Cited by
- 1,771
- References
- 30
- Citations by year
- 2026: 51 · 2025: 48 · 2024: 68 · 2023: 93 · 2022: 98 · 2021: 102 · 2020: 114 · 2019: 115 · 2018: 138 · 2017: 150 · 2016: 154 · 2015: 172 · 2014: 215 · 2013: 196 · 2012: 53
- FWCI
- 82.21
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (R01CA166480, U54CA112962, P50CA093683, UM1CA186709)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- RAF inhibitors, vemurafenib, drug resistance, tumor microenvironment, stromal cells, hepatocyte growth factor, MAPK signaling, PI3K/Akt signaling, combination therapy, co-culture model, targeted therapy, non-specific immunity, cancer cell lines, proteomics, immunohistochemistry, immunofluorescence
- MeSH terms
- Vemurafenib, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Humans, Indoles, Melanoma, Mutation, Prognosis, Sulfonamides, Signal Transduction, Stromal Cells, Hepatocyte Growth Factor, Coculture Techniques, Drug Resistance, Neoplasm, Proto-Oncogene Proteins c-met, Phosphatidylinositol 3-Kinases, Proteomics, Cell Line, Tumor, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Molecular Targeted Therapy, Tumor Microenvironment
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