Improving pharmacological targeting of AKT in melanoma.

Targeting AKT with pharmacological agents inhibiting this protein in the melanoma clinic is ineffective. This is a major contradiction considering the substantial preclinical data suggesting AKT as an effective target. Various approaches have been undertaken to unravel this contradiction and drug combinations sought that could resolve this concern. We have shown that genetic targeting AKT3 or WEE1 can be effective for inhibiting tumor growth in preclinical animal models. However, no one has examined whether combining pharmacological agents targeting each of these enzymes could be more effective than inhibiting each alone and enhance the efficacy of targeting AKT in melanoma. This report shows that combining the AKT inhibitors (AZD5363 or MK1775) with the WEE1 inhibitor, AZD5363, can synergistically kill cultured melanoma cells and decrease melanoma tumor growth by greater than 90%. Co-targeting AKT and WEE1 led to enhanced deregulation of the cell cycle and DNA damage repair pathways by modulating the transcription factors p53 and FOXM1, as well as the proteins whose expression is regulated by these two proteins. Thus, this study identifies a unique combination of pharmacological agents and the ratio needed for efficacy that could be used to potentially improve the therapeutic effectiveness of targeting AKT in the clinic.