MerTK inhibition is a novel therapeutic approach for glioblastoma multiforme

• Published in: Oncotarget 2014-03, Vol.5 (5), p.1338-1351
• Main Authors: Knubel, Kristina H, Pernu, Ben M, Sufit, Alexandra, Nelson, Sarah, Pierce, Angela M, Keating, Amy K
• Format: Article
• Language: English
• Subjects: Anilides - pharmacology; Anilides - therapeutic use; Animals; c-Mer Tyrosine Kinase; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases - metabolism; Glioblastoma - drug therapy; Glioblastoma - pathology; Humans; Mice; Neoplasm Invasiveness; Phosphorylation - drug effects; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Quinolines - pharmacology; Quinolines - therapeutic use; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - genetics; Receptor Protein-Tyrosine Kinases - metabolism; Research Paper; RNA, Small Interfering - therapeutic use; Signal Transduction - drug effects
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.1793

Glioblastoma is an aggressive tumor that occurs in both adult and pediatric patients and is known for its invasive quality and high rate of recurrence. Current therapies for glioblastoma result in high morbidity and dismal outcomes. The TAM subfamily of receptor tyrosine kinases includes Tyro3, Axl, and MerTK. Axl and MerTK exhibit little to no expression in normal brain but are highly expressed in glioblastoma and contribute to the critical malignant phenotypes of survival, chemosensitivity and migration. We have found that Foretinib, a RTK inhibitor currently in clinical trial, inhibited phosphorylation of TAM receptors, with highest efficacy against MerTK, and blocked downstream activation of Akt and Erk in adult and pediatric glioblastoma cell lines, findings that are previously unreported. Survival, proliferation, migration, and collagen invasion were hindered in vitro. Foretinib treatment in vivo abolished MerTK phosphorylation and reduced tumor growth 3-4 fold in a subcutaneous mouse model. MerTK targeted shRNA completely prevented intracranial and subcutaneous glioma growth further delineating the impact of MerTK inhibition on glioblastoma. Our findings provide additional target validation for MerTK inhibition in glioblastoma and demonstrate that robust MerTK inhibition can be achieved with the multi-kinase inhibitor Foretinib as an innovative and translational therapeutic approach to glioblastoma.