Akt targeting as a strategy to boost chemotherapy efficacy in non-small cell lung cancer through metabolism suppression.
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.
Aix-Marseille Université, Inserm UMR_S 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de pharmacie, Marseille, France.|Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Randwick, NSW, Australia.
Marion
M
Le Grand
Aix-Marseille Université, Inserm UMR_S 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de pharmacie, Marseille, France.
Raphael
R
Berges
Aix-Marseille Université, Inserm UMR_S 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de pharmacie, Marseille, France.|Metronomics Global Health Initiative, Marseille, France.
Eddy
E
Pasquier
Aix-Marseille Université, Inserm UMR_S 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de pharmacie, Marseille, France.
Marie-Pierre
MP
Montero
Centre de Recherche en Cancérologie de Marseille (CRCM), Aix-Marseille Université, Inserm U1068, Institut Paoli-Calmettes, 13009 Marseille, France.
Laurence
L
Borge
Centre de Recherche en Cancérologie de Marseille (CRCM), Aix-Marseille Université, Inserm U1068, Institut Paoli-Calmettes, 13009 Marseille, France.
Alice
A
Carrier
Centre de Recherche en Cancérologie de Marseille (CRCM), Aix-Marseille Université, Inserm U1068, Institut Paoli-Calmettes, 13009 Marseille, France.
Sophie
S
Vasseur
Aix-Marseille Université, Inserm UMR_S 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de pharmacie, Marseille, France.|Assistance Publique - Hopitaux de Marseille (AP-HM), Marseille, France.
Veronique
V
Bourgarel
Aix-Marseille Université, Inserm UMR_S 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de pharmacie, Marseille, France.
Duje
D
Buric
Aix-Marseille Université, Inserm UMR_S 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de pharmacie, Marseille, France.|Metronomics Global Health Initiative, Marseille, France.|Service d'Hématologie &Oncologie Pédiatrique, AP-HM, Marseille, France.
Nicolas
N
André
Aix-Marseille Université, Inserm UMR_S 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de pharmacie, Marseille, France.|Assistance Publique - Hopitaux de Marseille (AP-HM), Marseille, France.
Diane
D
Braguer
Aix-Marseille Université, Inserm UMR_S 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de pharmacie, Marseille, France.
Manon
M
Carré
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D018929:Cell Culture Techniques; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects*; D006019:Glycolysis; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D010767:Phosphorylcholine; C105905:perifosine; D051057:Proto-Oncogene Proteins c-akt; D017239:Paclitaxel