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

Abstract

The secretion of hepatocyte growth factor by stromal cells in the tumour micro-environment can make melanoma resistant to RAF inhibitors, through the activation of the MET signalling pathway, but a combination of RAF and MET inhibitors can overcome this resistance. Targeted anticancer therapies are gaining ground in clinical applications as researchers begin to understand the genetic changes underlying tumorigenesis and the factors that determine an individual patient's response to a drug. However, resistance is a challenging problem in most clinical trials of targeted therapies. Two complementary papers show that the secretion of growth factors from the tumour microenvironment can cause resistance to a range of anticancer drugs, through their ability to drive tumour growth by activating redundant signalling pathways. Both papers provide evidence that stromal production of hepatocyte growth factor can confer resistance to a class of drugs called BRAF inhibitors, such as vemurafenib, in patients with melanoma, through activation of the MET signalling pathway. They show that a combination of BRAF and MET inhibitors can overcome resistance, suggesting that this combination should be tested in patients with melanoma. 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 resistance1,2,3,4. 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.