111 Exploring Novel PI3K-AKT-MTOR Therapy Inhibition as a Treatment for Braf-Mutant Melanoma

Even with the emergence of new melanoma therapies, melanoma progression and metastasis is still the leading cause of death for those suffering from skin cancer (Liu, et al. 2014). There is only a 15-20% five-year survival rate for Stage IV melanoma, thus proving the need for new target therapies for melanoma. The phosphatidylinositol-3’-kinases (PI3K) and mitogen-activated protein kinase (MAPK) pathways play a significant role in cell proliferation in normal and cancer cells. PI3K and MAPK phosphorylate downstream effectors that regulate many biochemical processes during cell proliferation. In the MAPK pathway, a protein kinase called BRAF is the most commonly mutated proto-oncogene found in melanoma metastasis. However, mutation of this gene alone does not lead to melanomagenesis (Parkman, et al. 2021). Instead, melanomagenesis requires other mutations in various cell proliferation pathways such as the PI3K pathway. Some of the downstream effectors of the PI3K pathway are AKT and serum-and-glucocorticoid-regulated kinase (SGK). AKT has many roles in cell proliferation but most notably promotes activation of mTORC1, a protein that onsets cell proliferation. SGK is highly homologous to AKT. It has many of the same downstream effectors and promotes the activation of mTORC1 (Sommer, et al. 2013). Many current melanoma therapies target the MAPK pathway and particularly the commonly mutated BRAF protein. These therapies have shown success in inhibiting the MAPK pathway; nevertheless, the PI3K pathway is resistant to these therapies and remains active and able to continue cell growth. To combat the activation of the PI3K pathway, therapeutics have been developed to inhibit AKT and PI3K. However, the PI3K and AKT-targeted therapeutics are not successful in reducing the progression of melanoma metastasis and thus have not been FDA-approved. When AKT is genetically inhibited, overexpression of SGK occurs and can rescue the knockdown of AKT (unpublished data from the Holmen lab). Therefore, to decrease the proliferation effect of the PI3K pathway, the combination of inhibition of AKT and SGK is warranted. We report pharmacological inhibitors against both AKT and SGK to decrease melanoma cell proliferation in vitro. Furthermore, the combination of AKT + SGK inhibition resulted in decreased tumor progression and increased overall survival (p=0.0031) in a BRAFV600E-driven immunocompetent mouse model of melanoma. These findings demonstrate that dual targeting of SGK and AKT may represent a novel therapeutic strategy to diminish tumor growth.