Combined inhibition of PI3K and Src kinases demonstrates synergistic therapeutic efficacy in clear-cell renal carcinoma
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Caroline Roelants1,2, Sofia Giacosa1, Catherine Pillet3, Rémi Bussat1, Pierre Champelovier4, Olivier Bastien5, Laurent Guyon1, Valentin Arnoux4, Claude Cochet1 and Odile Filhol1
1Université Grenoble-Alpes, Inserm U1036, CEA, BIG-BCI, Grenoble, France
2Inovarion, Paris, France
3Université Grenoble-Alpes, Inserm U1038, CEA, BIG-BGE, Grenoble, France
4Centre Hospitalier Université Grenoble-Alpes, CS 10217, Grenoble, France
5Université Grenoble-Alpes, CNRS-CEA-INRA, Laboratoire de Physiologie Cellulaire et Végétale, Grenoble, France
Filhol Odile, email: [email protected]
Keywords: kidney cancer; synthetic lethality; 3D culture; protein kinase; targeted combinational therapy
Received: January 26, 2018 Accepted: June 12, 2018 Published: July 10, 2018
Potent inhibitors of PI3K (GDC-0941) and Src (Saracatinib) exhibit as individual agents, excellent oral anticancer activity in preclinical models and have entered phase II clinical trials in various cancers. We found that PI3K and Src kinases are dysregulated in clear cell renal carcinomas (ccRCCs), an aggressive disease without effective targeted therapies. In this study we addressed this challenge by testing GDC-0941 and Saracatinib as either single agents or in combination in ccRCC cell lines, as well as in mouse and PDX models. Our findings demonstrate that combined inhibition of PI3K and Src impedes cell growth and invasion and induces cell death of renal carcinoma cells providing preclinical evidence for a pairwise combination of these anticancer drugs as a rational strategy to improve renal cancer treatment.
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