title: The FAK scaffold inhibitor C4 disrupts FAK-VEGFR-3 signaling and inhibits pancreatic cancer growth.
abstract: Even with successful surgical resection and perioperative chemotherapy and radiation, pancreatic ductal adenocarcinoma (PDA) has a high incidence of recurrence. Tumor cell survival depends on activation of signaling pathways that suppress the apoptotic stimuli of invasion and metastasis. Focal adhesion kinase (FAK) is a critical signaling molecule that has been implicated in tumor cell survival, invasion and metastasis. We have previously shown that FAK and vascular endothelial growth factor receptor 3 (VEGFR-3) are overexpressed in cancer cells and physically interact to confer a significant survival advantage. We subsequently identified a novel small molecule inhibitor C4 that targeted the VEGFR-3-FAK site of interaction. In this study, we have shown that C4 disrupted the FAK-VEGFR-3 complexes in PDA cells. C4 treatment caused dose-dependent dephosphorylation and inactivation of the VEGFR-3 and FAK, reduction in cell viability and proliferation, cell cycle arrest and apoptosis in PDA cells. C4 increased the sensitivity of tumor cells to gemcitabine chemotherapy in vitro that lead to apoptosis at nanomolar concentrations of both drugs. C4 reduced tumor growth in vivo in subcutaneous and orthotopic murine models of PDA. The drug alone at low dose, decreased tumor growth; however, concomitant administration with low dose of gemcitabine had significant synergistic effect and led to 70% tumor reduction. Combination of C4 with gemcitabine had a prolonged cytostatic effect on tumor growth after treatment withdrawal. Finally, we report an anecdotal case of stage IV pancreatic cancer treated with gemcitabine in combination with C4 that showed a significant clinical response in primary tumor and complete clinical response in liver metastasis over an eight month period. Taken together, these results demonstrate that targeting the scaffolding function of FAK with a small-molecule FAK-VEGFR-3 inhibitor can be an effective therapeutic strategy against PDA.
authors.affiliation: Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY.
authors.forename: Elena
authors.initials: E
authors.lastname: Kurenova
authors.forename: Jianqun
authors.initials: J
authors.lastname: Liao
authors.forename: Di-Hua
authors.initials: DH
authors.lastname: He
authors.forename: Darrell
authors.initials: D
authors.lastname: Hunt
authors.forename: Michael
authors.initials: M
authors.lastname: Yemma
authors.forename: Wiam
authors.initials: W
authors.lastname: Bshara
authors.forename: Mukund
authors.initials: M
authors.lastname: Seshadri
authors.forename: William G
authors.initials: WG
authors.lastname: Cance
mesh_terms: D000818:Animals; 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; D002470:Cell Survival / Q000187:drug effects; D005029:Ethylenediamines / Q000494:pharmacology*; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011379:Prognosis; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D005029:Ethylenediamines; C004664:chloropyramine; D040321:Vascular Endothelial Growth Factor Receptor-3; D051416:Focal Adhesion Protein-Tyrosine Kinases