Hepatocyte growth factor (HGF) autocrine activation predicts sensitivity to MET inhibition in glioblastoma.
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.
Van Andel Research Institute, Grand Rapids, MI 49503, USA. qian.xie@vai.org
Qian
Q
Xie
Robert
R
Bradley
Liang
L
Kang
Julie
J
Koeman
Maria Libera
ML
Ascierto
Andrea
A
Worschech
Valeria
V
De Giorgi
Ena
E
Wang
Lisa
L
Kefene
Yanli
Y
Su
Curt
C
Essenburg
Dafna W
DW
Kaufman
Tom
T
DeKoning
Mark A
MA
Enter
Timothy J
TJ
O'Rourke
Francesco M
FM
Marincola
George F
GF
Vande Woude
D019898:Autocrine Communication / Q000502:physiology*; D015415:Biomarkers / Q000097:blood / Q000378:metabolism*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D066246:ErbB Receptors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000097:blood / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000097:blood / Q000378:metabolism*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D046228:Microarray Analysis; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011724:Pyridazines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014230:Triazoles / Q000494:pharmacology
C547925:6-(6-(1-methyl-1H-pyrazol-4-yl)-(1,2,4)triazolo(4,3-b)pyridazin-3-ylsulfanyl)quinoline; D015415:Biomarkers; D017931:DNA Primers; D011724:Pyridazines; D014230:Triazoles; D017228:Hepatocyte Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met