Abstract 427: Newer generation mTOR inhibition represents effective therapeutic strategy for BRAF-mutant melanoma

Abstract

Despite the advent of novel therapies, the five year survival rate for Stage IV melanoma remains at only 30%. This highlights the critical need for new therapeutics to treat this refractory disease. Aberrant activation of the PI3K-AKT pathway is common in melanoma, but efforts to drug this pathway have proven largely ineffective in clinical trials. In our study, we observed that pharmacological inhibition of AKT was ineffective whereas genetic silencing of all three AKT paralogs significantly abrogated melanoma cell growth and led to apoptosis through effects on mTORC signaling. This phenotype could be rescued by overexpression of AKT but was dependent on kinase activity. Interestingly, expression of the serine/threonine kinase SGK1 was increased following genetic suppression of AKT but only expression of activated SGK1 could rescue the lethal effect of AKT knockdown. SGK1 also increases tumor growth and decreases survival in a BRAFV600E-driven mouse model of melanoma. Despite our results suggesting that key proliferation of melanoma cells is through effects on mTOR, phase II clinical trials of mTOR inhibitors have not shown clinical advantage. This may be due to multiple reasons: firstly, mTOR inhibitors, such as rapamycin, function by destabilization of the mTORC1-Raptor complex while leaving the mTORC2-Rictor complex, intact. Rictor enables mTORC2 to directly phosphorylate Ser473, and facilitates Thr308 phosphorylation by PDK1. As both AKT and SGK are phosphorylated by mTORC2 and PDK1 to facilitate downstream signaling through mTORC1, residual activity of mTOR incompletely suppressed by rapamycin may still be sufficient to drive melanoma progression. Thus, we evaluated second and third generation mTORC inhibitors, including a dual PI3K/mTOR inhibitor, that target both mTORC1 and 2 complexes and lead to sustained suppression of PI3K>AKT signaling. The dual PI3K/mTORC inhibitor, Paxalisib, significantly reduced cell proliferation greater than combination AKT/SGK inhibition and resulted in increased overall survival in a BRAF-driven immunocompetent mouse model of melanoma (p=0.0003 vs vehicle). These results allow insight into compensatory signaling networks upon AKT inhibition and suggest that dual targeting of PI3K and both mTOR complexes may represent an effective and tolerable therapeutic strategy in this disease that could further be combined with standard of care targeted therapy. Citation Format: Gennie L. Parkman, Tursun Turapov, David Kircher, William Burnett, Christopher Stehn, Kayla O'Toole, Katie Culver, Ashley Chadwick, Riley Elmer, Ryan Flaherty, Mona Foth, Karly Stanley, Robert Andtbacka, David Lum, Robert Judson-Torres, Martin McMahon, Sheri Holmen. Newer generation mTOR inhibition represents effective therapeutic strategy for BRAF-mutant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 427.