Anti-cancer activity of NVP-TAE226, a potent dual FAK/IGF-IR kinase inhibitor, against pancreatic carcinoma

13162 Background: Focal adhesion kinase (FAK) is a non-receptor cytoplasmic tyrosine kinase that regulates multiple cell functions. Elevated expression levels of FAK have been detected in various tumor samples and are closely correlated with invasive potential. Activation of integrins and the growth factor receptors result in FAK autophosphorylation at Y397 and the presentation of suitable binding sites for proteins containing either SH2 or phosphotyrosine binding domains. Recent evidences suggest that FAK plays important roles in cancer cell proliferation and survival. IGF-IR function is required for tumor cell survival, but dispensable for survival of normal cells. Therefore, a dual inhibitor of both kinases may selectively block the growth, migration, and survival of FAK- and IGF-IR- expressing tumor cells compared to proliferating and migrating normal cells. Methods: In this study, anti-cancer activity of NVP-TAE226 that is identified as a potent and selective FAK inhibitor was evaluated in cancer cell lines panel and MIA PaCa-2 pancreatic carcinoma in vivo model. Results: Mean GI50 value of NVP-TAE226 against 37 cancer cell lines was 0.76 μmole/L. Inhibition of cancer cell proliferation was not affected by expression of P-glycoprotein, suggesting that NVP-TAE226 is not served as a substrate of P-glycoprotein. Oral administration of NVP-TAE226 efficiently inhibited MIA PaCa-2 human pancreatic tumor growth at all doses tested. Tumor stasis was observed at a dose of 30 mg/kg, qd for 7×/week and tumor regression was observed at a dose of 100 mg/kg, qd for 5×/week. All animals tolerated NVP-TAE226 treatment up to 100 mg/kg, 5×/wk, qd, po for 2 weeks with no body weight loss. Inhibition of downstream signaling such as phosphorylation of Akt at Serine473 was accompanied by inhibition of FAK phosphorylation in human pancreatic carcinoma cell lines. Conclusions: NVP-TAE226 is a novel class of selective and small molecule kinase inhibitors with a potent in vivo activity and potential therapeutic application. No significant financial relationships to disclose.