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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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“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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“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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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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