Abstract 2077: Selective MET kinase inhibition in MET-dependent glioma models

Abstract

Abstract Background - Grade IV diffuse gliomas (glioblastomas) are notoriously difficult to treat. Many studies aim at targeting tumor-specific aberrations, such as mutations in genes encoding oncogenic receptor tyrosine kinases (RTKs). Of high interest as a tumor target in diffuse glioma is the RTK MET, which is amplified in a significant proportion of glioblastomas, and a number of MET inhibitors have been developed. However, most RTK inhibitors available in the clinic today, including those inhibiting MET, are not entirely selective and inhibit additional kinases at the doses used. They therefore may induce potentially undesired off-target effects, such as blood-brain barrier normalization in the case of concomitant VEGFR2 inhibition. Methods – We studied the effects of the novel, selective MET-kinase inhibitor (Compound A) and the combined VEGFR2/RET/MET inhibitor cabozantinib on MET activation and proliferation in the MET-amplified E98 astrocytoma cell line in vitro, using western blot analysis and MTT proliferation assays. Effects of compound A were also studied in mice carrying orthotopic xenografts of the same E98 cell line. Survival was monitored and effects of MET inhibition were investigated by immunohistochemistry using phospho-specific antibodies. Results – E98 cells were highly sensitive to treatment with Compound A in vitro (IC50~9.4 nM). Furthermore, Compound A effectively inhibited phosphorylation of MET in orthotopic E98 xenografts. In contrast, we have previously shown that after treatment with cabozantinib in the same model the high levels of phosphorylated MET were maintained. While treatment with Compound A significantly prolonged the survival of E98-xenograft bearing mice, tumors still developed and showed extensive AKT phosphorylation in the absence of MET phopshorylation, suggesting in vivo therapy resistance mechanisms. Interestingly, resistance to Compound A was not seen in vitro in an E98 cell line derived from Compound A-resistant tumor xenografts. Conclusions – Compound A is a promising, highly selective MET kinase inhibitor with activity against gliomas with constitutive MET signaling. Selective MET kinase inhibitors may be more suited for treatment of glioma than combined VEGFR2/MET inhibitors, as the latter may induce vessel normalization resulting in poor tumor penetration. Similar to clinical experience, E98 tumor-bearing mice ultimately develop resistance to TKIs. Combination therapies targeting both MET and potential resistance pathways may be required to allow long-term tumor treatment. Citation Format: Corina van den Heuvel, Anna Navis, Houshang Amiri, Kiek Verrijp, Arend Heerschap, Karen Rex, Isabelle Dussault, Sean Caenepeel, Angela Coxon, Pieter Wesseling, William Leenders. Selective MET kinase inhibition in MET-dependent glioma models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2077. doi:10.1158/1538-7445.AM2017-2077