HGF is overexpressed in nearly half of AML samples and leads to autocrine activation of MET.
Major finding: HGF is overexpressed in nearly half of AML samples and leads to autocrine activation of MET.
Clinical relevance: Single-agent MET inhibition with crizotinib induces compensatory HGF upregulation.
Impact: Ligand-induced receptor activation may be a mechanism of resistance to RTK inhibition in AML.
Most patients with acute myeloid leukemia (AML) eventually develop resistance to cytotoxic chemotherapy. To identify potential therapeutic targets, Kentsis and colleagues performed a short-hairpin RNA screen for genes specifically required for the proliferation and survival of AML cells. One of the highest-ranking genes was hepatocyte growth factor (HGF), encoding the ligand for the MET receptor tyrosine kinase (RTK). Elevated HGF levels associated with activation of MET were observed in 4 of 7 AML cell lines and 58 of 138 (42%) clinical samples tested, indicating that aberrant HGF and MET signaling is prevalent in AML. Genetic or pharmacologic inhibition of either HGF or MET suppressed cell growth and induced apoptosis in multiple AML cell lines, suggesting that HGF-expressing AML cells are dependent on autocrine activation of MET for survival. The authors treated AML cell lines with crizotinib, a small-molecule MET and ALK inhibitor, to specifically evaluate the effects of MET inhibition on AML cells, which do not express ALK. Crizotinib strongly inhibited the growth of HGF-expressing AML cell lines, but after 6 days of crizotinib treatment, cell growth and MET signaling recovered due to compensatory upregulation of HGF. In HGF-positive AML cells also harboring an activating fibroblast growth factor receptor 1 (FGFR1) translocation, combined inhibition of MET and FGFR1 prevented HGF upregulation, leading to sustained inhibition of MET activation and cell growth. Furthermore, combined MET and FGFR1 inhibition synergized to induce regression of disease in leukemic mice. Together, these findings implicate HGF-mediated activation of MET in the pathogenesis of AML and identify compensatory ligand upregulation as a possible general mechanism of RTK inhibitor resistance that may be overcome with combination therapy.