Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma

Despite recent advances in therapy, liver metastasis from melanoma is still associated with poor prognosis. Although targeting the mTOR signaling pathway exerts potent anti-tumor activity, little is known about specific mTORC2 inhibition regarding liver metastasis. Using the novel mTORC2 specific inhibitor JR-AB2-011, we show significantly reduced migration and invasion capacity by impaired activation of MMP2 in melanoma cells. In addition, blockade of mTORC2 induces cell death by non-apoptotic pathways and reduces tumor cell proliferation rate dose-dependently. Furthermore, a significant reduction of liver metastasis was detected in a syngeneic murine metastasis model upon therapy with JR-AB2-011 as determined by in vivo imaging and necropsy. Hence, our study for the first time highlights the impact of the pharmacological blockade of mTORC2 as a potent novel anti-cancer approach for liver metastasis from melanoma.

Automated summary

This study demonstrates the significant reduction in migration, invasion, and proliferation of melanoma cells upon specific inhibition of mTORC2 using the novel inhibitor JR-AB2-011, leading to cell death through non-apoptotic pathways. In a syngeneic murine metastasis model, therapy with JR-AB2-011 showed a remarkable decrease in liver metastasis, highlighting the potential of pharmacological blockade of mTORC2 as a novel anti-cancer approach for melanoma liver metastasis.