Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma

• Main Authors: Jessica Guenzle, Harue Akasaka, Katharina Joechle, Wilfried Reichardt, Aina Venkatasamy, Jens Hoeppner, Claus Hellerbrand, Stefan Fichtner-Feigl, Sven A. Lang
• Format: Article
• Language: English
• Published: MDPI AG 2021-12-01
• Series: International Journal of Molecular Sciences
• Subjects: mTORC2; melanoma; migration; metastasis
• Online Access: https://www.mdpi.com/1422-0067/22/1/30
• ISSN: 1661-6596; 1422-0067

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.