Abstract LB-223: Dissecting the therapeutic determinants of MET inhibition in Glioblastoma: HGF-autocrine loop predicts sensitivity to MET inhibitor

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Due to its invasive nature, glioblastoma (GBM) is the most aggressive brain cancer. Hepatocyte growth factor (HGF) binds to MET tyrosine kinase receptor and induces invasive tumor growth. As MET inhibitors are entering clinical trials against several types of cancer including GBM, it is compelling to identify therapeutic determinants which could indicate which patient subsets are suitable for this therapy. We investigated in vivo four types of GBM models for their sensitivity to MET (SGX523*) or EGFR (erlotinib*) inhibitors: 1) Tumors sustained by an HGF-autocrine loop; 2) tumors displaying paracrine HGF tumor growth; and 3) tumors with polysomy MET amplification. 4) In addition, GBM tumors with epidermal growth factor receptor (EGFR) amplification were included, as this occurs frequently in GBM patients and often in association with MET aberrancy. Of the four tumor types, we observed that HGF-autocrine loop expression correlates with p-MET levels in the HGF autocrine cell lines, which in turn are extremely sensitive to MET inhibition in vivo. Moreover, serum HGF levels in HGF-autocrine loop GBM xenografts correlate with MET inhibition. Paracrine HGF can enhance GBM growth in vivo , but they were not significantly sensitive to MET inhibition. In type 4, EGFR VIII amplification predicted sensitivity to erlotinib, but MET polysomy in the same tumor did not display MET activity and the cells did not show sensitivity to MET inhibition. We conclude that HGF-autocrine loop GBM tumors bear an activated MET signaling pathway that may be used to predict sensitivity to MET inhibitors in GBM patients. However, targeting MET alone may not be sufficient for treating GBM and the combination of MET with other RTK inhibitors, especially EGFR inhibitors should be considered. *SGX523, a selective small molecule MET inhibitor, was obtained from Eli Lilly and Company, Indianapolis IN. *Erlotinib inhibits EGFR and was a generous gift from OSI Pharmaceuticals, Long Island N.Y. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-223. doi:10.1158/1538-7445.AM2011-LB-223