Selective MET Kinase Inhibition in MET-Dependent Glioma Models Alters Gene Expression and Induces Tumor Plasticity

The receptor tyrosine kinase (RTK) MET represents a promising tumor target in a subset of glioblastomas. Most RTK inhibitors available in the clinic today, including those inhibiting MET, affect multiple targets simultaneously. Previously, it was demonstrated that treatment with cabozantinib (MET/VEGFR2/RET inhibitor) prolonged survival of mice carrying orthotopic patient-derived xenografts (PDX) of the MET-addicted glioblastoma model E98, yet did not prevent development of recurrent and cabozantinib-resistant tumors. To exclude VEGFR2 inhibition-inflicted blood–brain barrier normalization and diminished tumor distribution of the drug, we have now investigated the effects of the novel MET-selective inhibitor Compound A in the orthotopic E98 xenograft model. In vitro, Compound A proved a highly potent inhibitor of proliferation of MET-addicted cell lines. In line with its target selectivity, Compound A did not restore the leaky blood–brain barrier and was more effective than cabozantinib in inhibiting MET phosphorylation in vivo. Compound A treatment significantly prolonged survival of mice carrying E98 tumor xenografts, but did not prevent eventual progression. Contrasting in vitro results, the Compound A–treated xenografts displayed high levels of AKT phosphorylation despite the absence of phosphorylated MET. Profiling by RNA sequencing showed that in vivo transcriptomes differed significantly from those in control xenografts.
Implications: Collectively, th...

Source: Molecular Cancer Research - October 31, 2017 Category: Cancer & Oncology Authors: van den Heuvel, C. N. A. M., Navis, A. C., de Bitter, T., Amiri, H., Verrijp, K., Heerschap, A., Rex, K., Dussault, I., Caenepeel, S., Coxon, A., Span, P. N., Wesseling, P., Hendriks, W., Leenders, W. P. J. Tags: Oncogenes and Tumor Suppressors Source Type: research