Modeling tandem AAG8‐MEK inhibition in melanoma cells

Drug resistance presents a challenge to the treatment of cancer patients, especially for melanomas, most of which are caused by the hyperactivation of MAPK signaling pathway. Innate or acquired drug‐resistant relapse calls for the investigation of the resistant mechanisms and new anti‐cancer drugs to provide implications for the ultimate goal of curative therapy. Aging‐associated gene 8 ( AAG 8, encoded by the SIGMAR 1 gene) is a chaperone protein profoundly elaborated in neurology. However, roles of AAG 8 in carcinogenesis remain unclear. Herein, we discover AAG 8 antagonists as new MEK inhibitors in melanoma cells and propose a novel drug combination strategy for melanoma therapy by presenting the experimental evidences. We report that specific antagonism of AAG 8, efficiently suppresses melanoma cell growth and migration through, at least in part, the inactivation of the RAS ‐ CRAF ‐ MEK signaling pathway. We further demonstrate that melanoma cells that are resistant to AAG 8 antagonist harbor refractory CRAF ‐ MEK activity. MEK acts as a central mediator for anti‐cancer effects and also for the resistance mechanism, leading to our proposal of tandem AAG 8‐ MEK inhibition in melanoma cells. Combination of AAG 8 antagonist and very low concentration of a MEK inhibitor synergistically restricts the growth of drug‐resistant cells. These data collectively pinpoint AAG 8 as a potential target and delineate a promising drug combination strategy for melanoma therapy.