Hepatocyte growth factor (HGF) autocrine activation predicts sensitivity to MET inhibition in glioblastoma

Qian Xie, Robert Bradley, Liang Kang, Julie Koeman, Maria Libera Ascierto, Andrea Worschech, Valeria De Giorgi, Ena Wang, Lisa Kefene, Yanli Su, Curt Essenburg, Dafna W. Kaufman, Tom DeKoning, Mark A. Enter, Timothy J. O'Rourke, Francesco M. Marincola, George F. Vande Woude

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Abstract

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.

Original languageEnglish
Pages (from-to)570-575
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number2
DOIs
Publication statusPublished - 10 Jan 2012
Externally publishedYes

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Keywords

  • Hepatocyte growth factor-autocrine loop
  • Molecular marker
  • Oncogene addiction
  • Targeted therapy

ASJC Scopus subject areas

  • General

Cite this

Xie, Q., Bradley, R., Kang, L., Koeman, J., Ascierto, M. L., Worschech, A., De Giorgi, V., Wang, E., Kefene, L., Su, Y., Essenburg, C., Kaufman, D. W., DeKoning, T., Enter, M. A., O'Rourke, T. J., Marincola, F. M., & Vande Woude, G. F. (2012). Hepatocyte growth factor (HGF) autocrine activation predicts sensitivity to MET inhibition in glioblastoma. Proceedings of the National Academy of Sciences of the United States of America, 109(2), 570-575. https://doi.org/10.1073/pnas.1119059109