BMS-754807, a small-molecule inhibitor of insulin-like growth factor-1 receptor/insulin receptor, enhances gemcitabine response in pancreatic cancer.

Abstract

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 μmol/L to 75 nmol/L for AsPC-1, from 3 μmol/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-754807+gemcitabine 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 = 0.03), with gemcitabine 28 days (P = 0.05), and in the BMS-754807+gemcitabine combination group, 41 days (P = 0.007). The strong antitumor activity of BMS-754807 in experimental PDAC supports the potential of BMS-754807-induced mechanisms for clinical PDAC therapy.

• Authors: Niranjan Awasthi, Changhua Zhang, Winston Ruan, Margaret A Schwarz, Roderich E Schwarz
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 11 Issue 12 Pg. 2644-53 (Dec 2012) ISSN: 1538-8514 [Electronic] United States
• PMID: 23047891 (Publication Type: Journal Article)

Chemical References

• BMS 754807
• Pyrazoles
• Triazines
• Deoxycytidine
• Receptor, IGF Type 1
• Gemcitabine

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Pancreatic Ductal (drug therapy, metabolism, pathology)
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Deoxycytidine (administration & dosage, analogs & derivatives, pharmacology)
• Drug Synergism
• Female
• Humans
• Immunohistochemistry
• Mice
• Mice, Nude
• Mice, SCID
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)
• Pyrazoles (administration & dosage, pharmacology)
• Random Allocation
• Receptor, IGF Type 1 (antagonists & inhibitors, metabolism)
• Signal Transduction
• Triazines (administration & dosage, pharmacology)
• Xenograft Model Antitumor Assays
• Gemcitabine