Cited by 1,771Melanoma and MAPK PathwaysCancer Cells and MetastasisColorectal Cancer Treatments and Studies

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Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion

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Straussman, Ravid, Morikawa, Teppei, Shee, Kevin, Barzily-Rokni, Michal, Qian, Zhi Rong, Du, Jinyan, Davis, Ashli, Mongare, Margaret M., Gould, Joshua, Frederick, Dennie T., Cooper, Zachary A., Chapman, Paul B., Solit, David B., Ribas, Antoni, Lo, Roger S., Flaherty, Keith T., Ogino, Shuji, Wargo, Jennifer A., Golub, Todd R.·2012·Nature

DOI 10.1038/nature11183PMC PMC3711467

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Abstract

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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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: Straussman, Ravid
Morikawa, Teppei
Shee, Kevin
Barzily-Rokni, Michal
Qian, Zhi Rong
Gould, Joshua
Frederick, Dennie T.
Cooper, Zachary A.
Chapman, Paul B.
Solit, David B.
Ribas, Antoni
Lo, Roger S.
Flaherty, Keith T.
Ogino, Shuji
Wargo, Jennifer A.
Golub, Todd R.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2012-07
Volume: 487
Issue: 7408
Pages: 500-504
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature11183
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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Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion

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