Tumor microenvironment induces innate RAF-inhibitor resistance through HGF secretion

The Eli and Edythe L. Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Nature (Impact Factor: 41.46). 07/2012; 487(7408):500-4. DOI: 10.1038/nature11183
Source: PubMed


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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    • "However culturing both cell types separately did not allow for any interaction between the tumour cells and the normal tissue. The direct and paracrine tumour–host interaction has been repeatedly demonstrated to affect chemo (Straussman et al., 2012) and radiosensitivity (Upreti et al., 2011), proliferation (Spink et al., 2006), angiogenesis (Wartenberg, 2001), cell adhesion (Chambers et al., 2011) and gene expression (L Berg et al., 2014). Spheroid co-cultures have been used to demonstrate differential response to local intravesical treatment in bladder cancer (Kilani et al., 2003, 2002). "
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    • "Intratumoral heterogeneity and consequences for targeted therapies tome 102 > n81 > January 2015 melanoma cells with BRAF (V600E) mutation [34], or fibroblastderived PDGF-C was shown to rescue anti-VEGFA treatment in murine lymphomas [35]. Other components of the stroma, like endothelial cells, can also function as suppliers of factors that can fuel resistance to treatment. "
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    • "Many mechanisms of resistance to BRAF inhibitors have been described, but in the majority of cases, it results from reactivation of the MEK/ERK pathway (Girotti et al., 2013; Johannessen et al., 2010; Nazarian et al., 2010; Shi et al., 2012; Straussman et al., 2012; Vergani et al., 2011; Villanueva et al., 2010; Wilson et al., 2012). Thus, amplification or upregulation of growth factors or receptor tyrosine kinases (RTKs), which signal through the SRCfamily kinases (SFKs), can lead to pathway reactivation and resistance . "
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