Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma.

Abstract

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.

• Authors: Jessica Guenzle, Harue Akasaka, Katharina Joechle, Wilfried Reichardt, Aina Venkatasamy, Jens Hoeppner, Claus Hellerbrand, Stefan Fichtner-Feigl, Sven A Lang
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 1 (Dec 22 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 33375117 (Publication Type: Journal Article)

Chemical References

• Protein Kinase Inhibitors
• Mechanistic Target of Rapamycin Complex 2
• Matrix Metalloproteinase 2

Topics

• Animals
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Enzyme Activation (drug effects)
• Humans
• Liver Neoplasms (metabolism, prevention & control, secondary)
• Male
• Matrix Metalloproteinase 2 (metabolism)
• Mechanistic Target of Rapamycin Complex 2 (antagonists & inhibitors, metabolism)
• Melanoma (drug therapy, metabolism, pathology)
• Mice, Inbred C57BL
• Protein Kinase Inhibitors (pharmacology)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays (methods)