title: Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion.
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.
authors: The Eli and Edythe L. Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors: Ravid
authors: R
authors: Straussman
authors: Teppei
authors: T
authors: Morikawa
authors: Kevin
authors: K
authors: Shee
authors: Michal
authors: M
authors: Barzily-Rokni
authors: Zhi Rong
authors: ZR
authors: Qian
authors: Jinyan
authors: J
authors: Du
authors: Ashli
authors: A
authors: Davis
authors: Margaret M
authors: MM
authors: Mongare
authors: Joshua
authors: J
authors: Gould
authors: Dennie T
authors: DT
authors: Frederick
authors: Zachary A
authors: ZA
authors: Cooper
authors: Paul B
authors: PB
authors: Chapman
authors: David B
authors: DB
authors: Solit
authors: Antoni
authors: A
authors: Ribas
authors: Roger S
authors: RS
authors: Lo
authors: Keith T
authors: KT
authors: Flaherty
authors: Shuji
authors: S
authors: Ogino
authors: Jennifer A
authors: JA
authors: Wargo
authors: Todd R
authors: TR
authors: Golub
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058990:Molecular Targeted Therapy; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D040901:Proteomics; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D059016:Tumor Microenvironment / Q000502:physiology*; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; C528407:PLX 4720; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf