title: 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.affiliation: Division of Surgical Oncology, Simmons Comprehensive Cancer Center, The University of Texas Southern Medical Center, Dallas, TX 75390, USA.
authors.forename: Niranjan
authors.initials: N
authors.lastname: Awasthi
authors.forename: Changhua
authors.initials: C
authors.lastname: Zhang
authors.forename: Winston
authors.initials: W
authors.lastname: Ruan
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Schwarz
authors.forename: Roderich E
authors.initials: RE
authors.lastname: Schwarz
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D014227:Triazines / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: C545990:BMS 754807; D011720:Pyrazoles; D014227:Triazines; D003841:Deoxycytidine; D017526:Receptor, IGF Type 1; D000093542:Gemcitabine