Inhibition of AKT-1 for the treatment of human non-small cell lung cancer
AKT is a serine-threonine kinase implicated in tumorigenesis as a central regulator of cellular growth, proliferation, survival, and metabolism. Activated AKT is overexpressed in 50-70% of non-small cell lung cancer (NSCLC) tumors and AKT inhibitors are currently under clinical investigation for the treatment of human NSCLC. However, these agents broadly target all three AKT isoforms and recent evidence suggests opposing roles in lung tumorigenesis where loss of Akt1 inhibits while the loss of Akt2 enhances tumor development in a transgenic mouse model. Based on these findings, we hypothesized that preferential inhibition of AKT-1 would warrant a more effective therapeutic strategy for NSCLC. Dose escalation studies revealed that an AKT-1 inhibitor A-674563 is significantly more effective at reducing NSCLC cell survival relative to a pan-AKT inhibitor MK-2206. Comparison of the downstream effects of the inhibitors suggests that altered cell cycle progression, isoform compensation, p-AKT-1 subcellular localization, and off-target CDK2 inhibition are likely vital to the improved efficacy of A-674563 over MK-2206.