| Description |
Current targeted therapies for melanoma aim to knock out proteins within pathways such as MAPK and PI3K-AKT. Despite extensive efforts, these therapies have not been effective in significantly reducing melanoma progression and metastasis. Many studies have focused on inhibiting the commonly mutated proto-oncogene BRAF (1). However, since melanoma progression does not occur with mutations in BRAF alone, other cell proliferation pathways need to be activated (4). For instance, if mutations in the PI3K-AKT pathway arise in conjunction with a BRAF mutation, this could lead to rapid melanoma formation (3). Efforts to inhibit the PI3K pathway have mainly focused on AKT, an important kinase in the pathway, but such therapies have failed to decrease overall melanoma cell proliferation. (5). This is partly due to the homology of AKT with another protein kinase, SGK. SGK shares many downstream effectors with AKT, including the activation of mTOR, which is an important protein in the cell proliferation pathway. To combat BRAF-mutant melanoma, we tested the combined inhibition of AKT and SGK, as well as the knockdown of the downstream effector mTOR. We report that pharmacological inhibitors against AKT and SGK decrease melanoma cell proliferation in vivo. However, the dual inhibition of PI3K and mTOR was found to be more effective. These findings demonstrate that dual targeting of PI3K and mTOR may represent a novel therapeutic strategy to abrogate melanoma growth. |
