Introduction: Receptor tyrosine kinases (RTK), such as c-Met and epidermal growth factor receptor (EGFR), are implicated in the malignant progression of glioblastoma. Studies show that RTK systems can co-modulate distinct and overlapping oncogenic downstream signaling pathways. EGFRvIII, a constitutively activated EGFR deletion mutant variant, leads to increased tumor growth and diminishes the tumor growth response to HGF:c-Met pathway inhibitor therapy. Conversely, activation of the c-Met pathway diminishes the tumor growth response to EGFR pathway inhibitors.
Methods: Previously we reported that EGFRvIII and c-Met pathway inhibitors synergize to inhibit tumor growth in isogenic GBM cell lines engineered to express EGFRvIII. To determine the broader relevance of these earlier findings, we examined the effects of combination c-Met and EGFR pathway inhibitor therapy on tumor growth responses, downstream second messenger systems, and stem-like tumor propogating cell populations in constitutively activated c-Met+/EGFRvIII+ primary human glioblastoma xenografts lines.
Results: We show that Crizotinib (c-Met pathway inhibitor) and Erlotinib (EGFR pathway inhibitor) in combination significantly inhibit tumor growth, phospho-EGFRvIII, phospho-Met, phospho-AKT, phospho-MAPK, and neurosphere growth in Mayo 39 and Mayo 59 primary GBM subcutaneous xenografts. The expression of the stem cell markers Nestin, Musashi, Olig 2 and Sox2 were also significantly down-regulated by c-Met inhibition, but no additive down-regulation was seen by co-treatment with Erlotinib.
Conclusions: These results are consistent with and corroborate our previous findings demonstrating that targeting these two parallel pathways with c-Met and EGFR inhibitor therapy provides substantial anti-tumor activity in glioblastoma models.
Patient Care: This research will improve patient care by demonstrating that targeting c-Met and EGFR pathways in glioblastoma xenograft models provides substantial anti-tumor activity.
Learning Objectives: By the conclusion of this session, participants should be able to describe the importance of the c-Met and EGFR pathway in glioblastoma and the benefit of targeting these two parallel pathways with c-Met and EGFR inhibitors in human glioblastoma xenograft models.
References: References:
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