Cooperative Blockade of CK2 and ATM Kinases Drives Apoptosis in VHL-Deficient Renal Carcinoma Cells through ROS Overproduction.

Kinase-targeted agents demonstrate antitumor activity in advanced metastatic clear cell renal cell carcinoma (ccRCC), which remains largely incurable. Integration of genomic approaches through small-molecules and genetically based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. The 786-O cell line represents a model for most ccRCC that have a loss of functional pVHL (von Hippel-Lindau). A multiplexed assay was used to study the cellular fitness of a panel of engineered ccRCC isogenic 786-O VHL- cell lines in response to a collection of targeted cancer therapeutics including kinase inhibitors, allowing the interrogation of over 2880 drug-gene pairs. Among diverse patterns of drug sensitivities, investigation of the mechanistic effect of one selected drug combination on tumor spheroids and ex vivo renal tumor slice cultures showed that VHL-defective ccRCC cells were more vulnerable to the combined inhibition of the CK2 and ATM kinases than wild-type VHL cells. Importantly, we found that HIF-2α acts as a key mediator that potentiates the response to combined CK2/ATM inhibition by triggering ROS-dependent apoptosis. Importantly, our findings reveal a selective killing of VHL-deficient renal carcinoma cells and provide a rationale for a mechanism-based use of combined CK2/ATM inhibitors for improved patient care in metastatic VHL-ccRCC.

Cancers. 2021 Feb 02*** epublish ***

Sofia Giacosa, Catherine Pillet, Irinka Séraudie, Laurent Guyon, Yann Wallez, Caroline Roelants, Christophe Battail, Bertrand Evrard, Frédéric Chalmel, Caroline Barette, Emmanuelle Soleilhac, Marie-Odile Fauvarque, Quentin Franquet, Clément Sarrazin, Nicolas Peilleron, Gaëlle Fiard, Jean-Alexandre Long, Jean-Luc Descotes, Claude Cochet, Odile Filhol

Interdisciplinary Research Institute of Grenoble, IRIG-Biosanté, University Grenoble Alpes, CEA, UMR 1292, F-38000 Grenoble, France., Inovarion, F-75005 Paris, France., Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail), University Rennes, UMR_S 1085, F-35000 Rennes, France., Centre Hospitalier Universitaire Grenoble Alpes, CS 10217, CEDEX 9, F-38043 Grenoble, France.