Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion
Menées sur des lignées cellulaires, ces deux études identifient des mécanismes de résistance aux inhibiteurs de tyrosine kinase
Drug resistance presents a challenge to the treatment of cancer patients.Many studies have focusedoncell-autonomous mechanisms of drug resistance. By contrast, we proposed that the tumour microenvironment confers innate resistance to therapy. Herewe 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 resistance1–4. Proteomic analysis showed that stromal cell secretion of hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the mitogenactivated 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 microenvironment can uncover important mechanisms underlying drug resistance.
Nature , résumé, 2011