A novel low molecular weight inhibitor of focal adhesion kinase and insulin-like growth factor-1 receptor, TAE226, inhibits glioma growth

Abstract

11505 Background: Glioblastomas are highly lethal cancers that resist current therapies. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase overexpressed in glioblastoma patient specimens that may promote glioma growth and invasion by increasing cellular adhesion, migration, invasion, proliferation. TAE226 is a novel low molecular weight inhibitor of several kinases that demonstrates in vitro activity primarily against FAK with activity against insulin-like growth factor-1 receptor (IGF1R) at higher concentrations. Methods: As FAK and IGF1R are potential molecular targets in glioblastomas, we examined the efficacy of TAE226 against human glioma cell lines and xenografts. Results: TAE226 inhibited the activating phosphorylation of FAK at submicromolar concentrations with residue specific preference. Downstream effectors (Akt and ERK) were inhibited at slightly higher concentrations. TAE226 demonstrated a concentration-dependent decrease in cellular proliferation with an associated G2 cell cycle arrest in multiple glioma cell lines, whereas TAE226 potently induced apoptosis in a concentration-dependent manner in only one of four cell lines tested. TAE226 also induced a concentration-dependent decrease in cellular adhesion, migration, and invasion. In preliminary animal studies, a limited course of orally administered TAE226 (100 mg/kg qd 5 days on/2 days off/5 days) was well tolerated with minimal weight loss. TAE226 induced a modest growth delay of human glioma xenografts grown in a subcutaneous location in athymic mice (3 to 4 days delay, p < 0.001). In addition, mice bearing orthotopic intracranial human glioma xenografts demonstrated a modest increase in median survival (3.5 days, p = 0.078). Despite the modest degree of the tumor responses, these results are superior to other low molecular weight inhibitors, such as epidermal growth factor receptor (EGFR) inhibitors. As glioma xenografts often grow without invasion, these results may underestimate the efficacy of targeting FAK as FAK plays a major role in tumor invasion. Conclusion: TAE226 demonstrates modest activity as monotherapy against malignant gliomas and warrants further investigation, potentially in combination with other therapies. [Table: see text]