Restoration of TRAIL-induced apoptosis in resistant human pancreatic cancer cells by a novel FAK inhibitor, PH11

P. Dao (1) , N. Smith (1) , Daniel Scott-Algara (2) , C. Garbay (1) , J.P. Herbeuval (1) , Huixiong Chen (1)

1 LCBPT - UMR 8601 - Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques
2 Régulation des Infections Rétrovirales

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) emerges as one of the most-promising experimental cancer therapeutic drugs and is currently being tested in clinical trials. However, both intrinsic and acquired resistance of human cancer cells to TRAIL-induced apoptosis poses a huge problem in establishing clinically efficient TRAIL therapies. To assess the regulation of TRAIL-resistance in human pancreatic cancer cells, we studied the TRAIL resistant pancreatic cell line PANC-1. We show that treatment with PH11, a novel Focal Adhesion Kinase (FAK) inhibitor in association with TRAIL rapidly induces apoptosis in TRAIL-resistant PANC-1 cells, but not in normal human fibroblast cells. To explain sensitization, we showed that PH11 restores TRAIL apoptotic pathway in PANC-1 cells through down-regulation of c-FLIP via inhibition of FAK and the phosphatidylinositol-3 kinase (PI3K)/AKT pathways. These findings suggest that this combined treatment may offer an attractive therapeutic strategy for safely and efficiently treating pancreatic cancer.

Keywords: FAK inhibitor; PI3K/AKT pathway; Pancreatic cancer cell lines; TRAIL; c-FLIP

Domains: Life Sciences [q-bio]; Immunology; Life Sciences [q-bio]; Immunology; Innate immunity

P. Dao, N. Smith, Daniel Scott-Algara, C. Garbay, J.P. Herbeuval, et al.. Restoration of TRAIL-induced apoptosis in resistant human pancreatic cancer cells by a novel FAK inhibitor, PH11. Cancer Letters, 2015, 360 (1), pp.48-59. ⟨10.1016/j.canlet.2015.02.016⟩. ⟨pasteur-02573704⟩