A-674563, a putative AKT1 inhibitor that also suppresses CDK2 activity, inhibits human NSCLC cell growth more effectively than the pan-AKT inhibitor, MK-2206

Abstract

AKT is a serine-threonine kinase implicated in tumorigenesis as a central regulator of cellular growth, proliferation, survival, and metabolism. Activated AKT is commonly overexpressed in non-small cell lung cancer (NSCLC) and accordingly AKT inhibitors are under clinical investigation for NSCLC treatment. Thus far, the AKT inhibitors being evaluated broadly target all three (1–3) AKT isoforms but recent evidence suggests opposing roles in lung tumorigenesis where loss of Akt1 inhibits while the loss of Akt2 enhances lung tumor development. Based on these findings, we hypothesized that selective inhibition of AKT-1 would be a more effective therapeutic strategy than pan-AKT inhibition for NSCLC treatment. Using six NSCLC cell lines, we found that the AKT-1 inhibitor, A-674563, was significantly more effective at reducing NSCLC cell survival relative to the pan-AKT inhibitor MK-2206. Comparison of the downstream effects of the inhibitors suggests that altered cell cycle progression and off-target CDK2 inhibition are likely vital to the improved efficacy of A-674563 over MK-2206.