Because oncogene MET and EGF receptor (EGFR) inhibitors are in clinical development against several types of cancer, including glioblastoma, it is important to identify predictive markers that indicate patient subgroups suitable for such therapies. We investigated in vivo glioblastoma models characterized by hepatocyte growth factor (HGF) autocrine or paracrine activation, or by MET or EGFR amplification, for their susceptibility to MET inhibitors. HGF autocrine expression correlated with high phospho-MET levels in HGF autocrine cell lines, and these lines showed high sensitivity to MET inhibition in vivo. An HGF paracrine environment may enhance glioblastoma growth in vivo but did not indicate sensitivity to MET inhibition. EGFRvIII amplification predicted sensitivity to EGFR inhibition, but in the same tumor, increased copies of MET from gains of chromosome 7 did not result in increased MET activity and did not predict sensitivity to MET inhibitors. Thus, HGF autocrine glioblastoma bears an activated MET signaling pathway that may predict sensitivity to MET inhibitors. Moreover, serum HGF levels may serve as a biomarker for the presence of autocrine tumors and their responsiveness to MET therapeutics.hepatocyte growth factor-autocrine loop | molecular marker | oncogene addiction | targeted therapy T he intrinsic ability of glioblastoma multiforme (GBM) tumor cells to invade normal brain tissue impedes complete surgical eradication and predictably results in early local recurrence and mortality. Understanding the molecular mechanisms of GBM invasiveness will lead to novel therapeutic strategies. The major signaling pathways driving GBM tumorigenesis and invasion are Ras-MAPK and AKT. Hepatocyte growth factor (HGF) binding to its receptor MET triggers this series of intracellular signaling, leading to tumor cell proliferation, invasion, survival, and angiogenesis (1-6). Aberrant MET activation can occur through numerous mechanisms, such as autocrine or paracrine stimulation, transcriptional regulation (7), ligand-independent or mutational activation (1, 8); MET amplification can be a major driver after acquired resistance to EGF receptor (EGFR) inhibitors (9), because of cross-talk with other receptor tyrosine kinase (RTK) family members.Most glioblastomas show MET overexpression, and some display HGF autocrine activation of the MET signaling pathway (10). Approximately 88% of GBM patients have an aberrant RTK/Ras-PI3K pathway activity. MET is located on chromosome 7q, and gains of chromosome 7 occur frequently in GBM. Also, though MET mutations are rare (11, 12), a high level of MET amplification is found in ∼4% of GBM tumors. Amplification of EGFR occurs in 45% of GBM tumors and could be associated with aberrant MET expression (11).HGF can also transcriptionally activate EGFR signaling in GBM cell lines (13), and EGFR variant III (EGFRvIII) can activate MET signaling (14), suggesting the importance of using a combination of MET and EGFR inhibitors in targeting GBM. EGFRvIII and MET inhibitors synergize against...

A randomized controlled trial is needed to further investigate these relationships.