Akt targeting as a strategy to boost chemotherapy efficacy in non-small cell lung cancer through metabolism
Marion Le Grand1,2, Raphael Berges1, Eddy Pasquier1,3
1Aix-Marseille Université, Inserm UMR_S 911, Centre de Recherche en Oncologie biologique et Oncopharmacologie, Faculté de pharmacie, Marseille, France.
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.
Insights
Combining Akt inhibitors with metronomic microtubule-targeting agents shows promise for non-small cell lung cancer therapy. This approach targets cancer cell metabolism and demonstrates synergistic effects, offering a new avenue for NSCLC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Metabolic reprogramming is a key feature of cancer, driven by genetic and epigenetic changes.
- The Akt kinase is frequently overexpressed in tumors, promoting glycolysis and offering a target for drug development.
- Non-small cell lung cancer (NSCLC) represents a significant portion of lung cancer cases, necessitating improved therapeutic strategies.
Purpose of the Study:
- To investigate the efficacy of inhibiting Akt activity in combination with other agents for NSCLC treatment.
- To explore the synergistic interactions between Akt inhibitors and Microtubule-Targeting Agents (MTAs) in NSCLC.
- To evaluate the therapeutic potential of combining metronomic paclitaxel with an anti-Akt agent.
Main Methods:
- Synergistic effects of Akt inhibitors and MTAs were assessed in cancer cell lines, including drug-resistant models.
- In vivo studies utilized chronic low-dose paclitaxel (metronomic scheduling) combined with the anti-Akt agent perifosine in NSCLC models.
- Mechanisms of action were investigated, focusing on apoptosis, cell cycle arrest, and metabolic pathways (glycolytic and mitochondrial).
Main Results:
- Akt inhibitors demonstrated synergistic activity with MTAs in various cancer cell lines, including those resistant to chemotherapy and anti-EGFR therapies.
- The combination of metronomic paclitaxel and perifosine proved to be the most effective and well-tolerated treatment against NSCLC in vivo.
- Perifosine enhanced paclitaxel's pro-apoptotic effects independently of cell cycle arrest, leading to sustained suppression of cancer cell metabolism.
Conclusions:
- Targeting cancer cell bioenergetics through combined therapies represents a novel and promising therapeutic strategy for NSCLC.
- The combination of metronomic MTAs and Akt inhibitors offers a strong foundation for future clinical trials in NSCLC.
- This study highlights the potential of combining metabolic targeting with established chemotherapy approaches for improved NSCLC outcomes.
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