Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2019; 10:2236.

Combined inhibition of PI3K and Src kinases demonstrates synergistic therapeutic efficacy in clear-cell renal carcinoma

Roelants Caroline, Giacosa Sofia, Pillet Catherine, Bussat Rémi, Champelovier Pierre, Bastien Olivier, Guyon Laurent, Arnoux Valentin, Cochet Claude and Filhol Odile _

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Oncotarget. 2018; 9:30066-30078. https://doi.org/10.18632/oncotarget.25700

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Abstract

Roelants Caroline1,2, Giacosa Sofia1, Pillet Catherine3, Bussat Rémi1, Champelovier Pierre4, Bastien Olivier5, Guyon Laurent1, Arnoux Valentin4, Cochet Claude1 and Filhol Odile1

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

Correspondence to:

Filhol Odile, email: odile.filhol-cochet@cea.fr

Keywords: kidney cancer; synthetic lethality; 3D culture; protein kinase; targeted combinational therapy

Received: January 26, 2018    Accepted: June 12, 2018    Published: July 10, 2018

ABSTRACT

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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