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

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.
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Contributor : Dominique Figarella-Branger <>
Submitted on : Thursday, April 19, 2018 - 2:16:01 PM
Last modification on : Sunday, September 26, 2021 - 3:10:59 AM

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Marion Le Grand, Raphael Berges, Eddy Pasquier, Marie-Pierre Montero, Laurence Borge, et al.. Akt targeting as a strategy to boost chemotherapy efficacy in non-small cell lung cancer through metabolism suppression.. Scientific Reports, Nature Publishing Group, 2017, pp.45136. ⟨10.1038/srep45136⟩. ⟨hal-01771176⟩



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