Abstract #1840: Dual tyrosine kinase inhibitor for focal adhesion kinase and insulin-like growth factor-I receptor (TAE226) leads to apoptosis in esophageal cancer by inhibiting AKT-mTOR survival signaling

Introduction: Receptor/non-receptor tyrosine kinases stimulate phosphatidylinositol-3-kinase (PI3K) and its downstream effectors such as AKT and mammalian target of rapamycin (mTOR). PI3K-AKT-mTOR signaling is well known to play a center role for cell growth and survival, and it is often upregulated in most of malignancies. Targeting molecules involved in this pathway has been a major strategy to develop a novel cancer treatment. TAE226 is a newly synthesized compound whose pharmacologic effect is a potent ATP competitive inhibition specific to focal adhesion kinase (FAK) and insulin-like growth factor-I receptor (IGF-IR), both of which are major tyrosine kinases upstream of AKT. In this study we focused upon the inhibitory effects of TAE226 on the survival signals and also assessed its antitumor effect in esophageal cancer, which is one of the most aggressive cancers in the world. Materials and Methods: Cultured esophageal cancer cells (SEG-1, FLO-1, BIC-1, TE-1, and T.Tn)were treated with TAE226 to assess its effect on cell proliferation and apoptosis in vitro. Western blot was carriedout to explore a participating signaling pathway for TAE226-inducedcell death. Furthermore, TAE226 was orally administered to subcutaneousxenograft animals to investigate its antitumor effect in vivo. Results: When esophageal cancercells were treated with TAE226, their proliferation was greatly inhibited in a dose-dependent fashion with an apparent structural change ofactin fiber and a loss of cell adhesion. Western blot analysis revealed that the activities of FAK,IGF-IR, and AKT were suppressed by TAE226 and subsequent dephosphorylationof BAD at Ser¹³⁶, mTOR (Ser2448), p70S6K (Thr389) and S6 (Ser240/244) occurred, resulting in caspase-mediated apoptosis. Furthermore, daily oral administrations of TAE226 significantly suppressed subcutaneous tumor growth in vivo. Conclusion: These results suggest that TAE226, a dual tyrosinekinase inhibitor for FAK and IGF-IR, can be a potential therapeutic agent for esophageal cancer treatment by a potent inhibition of PI3K-AKT-mTOR cell survival signaling.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1840.