Preclinical Development BMS-754807, a Small-Molecule Inhibitor of Insulin-like Growth Factor-1 Receptor/Insulin Receptor, Enhances Gemcitabine Response in Pancreatic Cancer

Gemcitabine has limited clinical benefits in pancreatic ductal adenocarcinoma (PDAC). Insulin-like growth factor (IGF) signaling proteins are frequently overexpressed in PDAC. The therapeutic potential of BMS-754807, a small-molecule inhibitor of IGF-type 1 receptor (IGF-1R) and insulin receptor (IR), and gemcitabine was evaluated in experimental PDAC. Cell proliferation and protein expression were measured by WST-1 assay and immunoblotting. Tumor growth and survival studies were conducted in murine xenografts. PDAC cells expressed phospho-IGF-1R protein. BMS-754807 and gemcitabine inhibited cell proliferation of PDAC cells; the combination of BMS-754807 with gemcitabine had additive effects. Addition of BMS-754807 decreased gemcitabine IC50 from 9.7 mmol/L to 75 nmol/L for AsPC-1, from 3 mmol/L to 70 nmol/L for Panc-1, from 72 to 16 nmol/L for MIA PaCa-2, and from 28 to 16 nmol/L for BxPC-3 cells. BMS-754807 caused a decrease in phospho-IGF-1R and phospho-AKT proteins in AsPC-1 and Panc-1 cells. BMS-754807 and gemcitabine caused an increase in PARP-1 and caspase-3 cleavage. Net tumor growth inhibition in BMS-754807, gemcitabine, and BMS-754807þgemcitabine groups was 59%, 35%, and 94% as compared with controls. Effects of therapy on intratumoral proliferation and apoptosis corresponded with tumor growth inhibition data. BMS-754807 also caused a decrease in phospho-IGF-1R and phospho-AKT in tumor tissue lysates. Median animal survival (controls: 21 days) with BMS-754807 was 27 days (P 1⁄4 0.03), with gemcitabine 28 days (P 1⁄4 0.05), and in the BMS-754807þgemcitabine combination group, 41 days (P 1⁄4 0.007). The strong antitumor activity of BMS-754807 in experimental PDAC supports the potential of BMS-754807-induced mechanisms for clinical PDAC therapy. Mol Cancer Ther; 11(12); 2644–53. 2012 AACR.