Synergy with combination of AKT inhibitor (MK-2206) and paclitaxel in head and neck squamous cell carcinoma.

Abstract

e13532 Background: Though there have been many advances in the treatment of HNSCC, the 5-year survival rate remains at 50%. This is partly due to molecular alterations such as the activation of the PI3k-AKT pathway in HNSCC, which has been associated with treatment failure. We stained human tissue samples and saw increased expression of p-AKT and pS6 in HNSCC compared to normal and dysplasia. This led us to investigate the role of the AKT inhibitor MK-2206 in combination with an already established chemotherapeutic agent, paclitaxel. Methods: Cell viability and Combination index were used to determine synergy in 4 HNSCC cell lines. PI exclusion and Annexin/PI staining were used to determine cell death and apoptosis, respectively. Autophagy was measured through changes in LC3BII protein levels using western blot analysis and a stably transfected GFP-LC3BII cell line was used to detect changes in protein localization under confocal microscopy. Results: All cell lines were sensitive to paclitaxel while only some were sensitive to MK-2206. However, there was effective synergy to the combination treatment in all cell lines. Apoptotic synergy was observed in some cell lines indicating that the combination stimulates cell death in the appropriate context. In one autophagy competent cell line, MK-2206 induced robust autophagy while paclitaxel blocked a latter step in the pathway leading to an accumulation of autophagosomes prior to induction of apoptosis. Conclusions: Paclitaxel and MK-2206 appears to be an effective combination in HNSCC possibly through their effect on autophagy trafficking, leading to an accumulation of autophagosomes and eventual apoptosis. Clinical trials examining this combination are warranted.