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Nature DOI:10.1038/nature11183

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

Publication TypeJournal Article
Year of Publication2012
AuthorsStraussman, R, Morikawa, T, Shee, K, Barzily-Rokni, M, Qian, ZRong, Du, J, Davis, A, Mongare, MM, Gould, J, Frederick, DT, Cooper, ZA, Chapman, PB, Solit, DB, Ribas, A, Lo, RS, Flaherty, KT, Ogino, S, Wargo, JA, Golub, TR
Date Published2012 Jul 26
KeywordsAntineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Cell Line, Tumor, Coculture Techniques, Drug Resistance, Neoplasm, Hepatocyte Growth Factor, Humans, Indoles, Melanoma, Molecular Targeted Therapy, Mutation, Phosphatidylinositol 3-Kinases, Prognosis, Protein Kinase Inhibitors, Proteomics, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-met, Signal Transduction, Stromal Cells, Sulfonamides, Tumor Microenvironment

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.


Alternate JournalNature
PubMed ID22763439
PubMed Central IDPMC3711467
Grant ListUM1 CA186709 / CA / NCI NIH HHS / United States
P50 CA093683 / CA / NCI NIH HHS / United States
U54CA112962 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
U54 CA112962 / CA / NCI NIH HHS / United States
P50CA093683 / CA / NCI NIH HHS / United States