Stromal cell–secreted HGF confers innate resistance to BRAF inhibition.
Major finding: Stromal cell–secreted HGF confers innate resistance to BRAF inhibition.
Clinical relevance: High plasma and stromal HGF levels were correlated with poor response to vemurafenib.
Impact: RAF inhibitors may be more effective when used in combination with inhibitors of HGF or MET.
Most kinase-addicted tumors have partial or complete innate resistance to targeted therapy. Straussman and colleagues hypothesized that the tumor environment plays a key role in mediating drug resistance, and they therefore systematically evaluated the stromal contribution to drug resistance by culturing cancer cell lines alone or in combination with human stromal cell lines in the presence of increasing doses of anticancer agents. Strikingly, the efficacy of most targeted therapies tested was diminished when cancer cells were cocultured with stromal cells due to the secretion of soluble factors. In another study, Wilson and colleagues similarly found that most kinase-addicted cancer cell lines they tested could be rescued from sensitivity to targeted therapies when exposed to several different soluble growth factors. In addition to identifying evidence for a general mode of drug resistance driven by the tumor microenvironment, both groups observed that hepatocyte growth factor (HGF) conferred resistance to the BRAF inhibitor vemurafenib on multiple BRAF-mutant melanoma cell lines through concurrent activation of the PI3K and MAPK pathways downstream of its receptor, MET. Furthermore, inhibition of MET with crizotinib restored sensitivity to vemurafenib in vitro and enhanced the effect of vemurafenib on melanoma xenograft tumor growth. In clinical samples, Wilson and colleagues observed that high pretreatment plasma HGF levels were predictive of worse progression-free and overall survival, and Straussman and colleagues found that HGF was frequently detected in stromal cells in pretreatment biopsy samples of BRAF-mutant melanomas and that patients with HGF-positive biopsies had a significantly poorer response to vemurafenib treatment. These findings may explain the high rate of innate resistance to vemurafenib in patients with BRAF-mutant melanoma and suggest that combining HGF- or MET-targeted therapy with BRAF inhibition may be a more effective therapeutic strategy.
Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR, Du J, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 2012;487:500–4.
Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 2012;487:505–9.
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