The DOI matches its Crossref record; 31 of the 31 references it cites were found in a registry or an index.
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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“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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“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]
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“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]
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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
Self-citationKalluri, R., & Zeisberg, M. (2006) · Nature Reviews Cancer · doi:10.1038/nrc1877 · Cited by 4,538
MET 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
Microenvironmental regulation of metastasis
Joyce, J. A., & Pollard, J. W. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2618 · Cited by 3,684
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-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 2,244
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-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
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 1,875
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
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
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 1,289
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
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
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
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
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
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
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
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 324
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
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 233
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
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
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
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
Liu, C., Park, M., & Tsao, M. (1992) · PubMed · Cited by 142
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 122
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
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
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
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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
The biology and function of fibroblasts in cancer
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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
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 3,191
Metadata
- 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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