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Akt targeting as a strategy to boost chemotherapy efficacy in non-small cell lung cancer through metabolism suppression

2017; Nature Portfolio; Volume: 7; Issue: 1 Linguagem: Inglês

10.1038/srep45136

2045-2322

Marion Le Grand, Raphaël Bergès, Eddy Pasquier, Marie-Pierre Montero, Laurence Borge, Alice Carrier, Sophie Vasseur, Véronique Bourgarel‐Rey, Duje Buric, Nicolás André, Diane Braguer, Manon Carré,

Cancer, Hypoxia, and Metabolism

Abstract Metabolic reprogramming is a hallmark of cancer development, mediated by genetic and epigenetic alterations that may be pharmacologically targeted. Among oncogenes, the kinase Akt is commonly overexpressed in tumors and favors glycolysis, providing a rationale for using Akt inhibitors. Here, we addressed the question of whether and how inhibiting Akt activity could improve therapy of non-small cell lung cancer (NSCLC) that represents more than 80% of all lung cancer cases. First, we demonstrated that Akt inhibitors interacted synergistically with Microtubule-Targeting Agents (MTAs) and specifically in cancer cell lines, including those resistant to chemotherapy agents and anti-EGFR targeted therapies. In vivo , we further revealed that the chronic administration of low-doses of paclitaxel - i.e . metronomic scheduling - and the anti-Akt perifosine was the most efficient and the best tolerated treatment against NSCLC. Regarding drug mechanism of action, perifosine potentiated the pro-apoptotic effects of paclitaxel, independently of cell cycle arrest, and combining paclitaxel/perifosine resulted in a sustained suppression of glycolytic and mitochondrial metabolism. This study points out that targeting cancer cell bioenergetics may represent a novel therapeutic avenue in NSCLC, and provides a strong foundation for future clinical trials of metronomic MTAs combined with Akt inhibitors.