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.

Role of mammalian target of rapamycin complex 2 in primary and secondary liver cancer

“…Rictor mRNA and protein were shown to be overexpressed in invasive melanoma[ 100 ] and to be significantly enhanced in metastatic compared with nonmetastatic melanoma[ 101 ]. Consistent with those findings, siRNA-mediated Rictor knockdown as well as pharmacological inhibition of mTORC2 not only led to reduced tumor cell motility, migration, and invasion in vitro [ 100 , 101 ] but also reduced melanoma liver metastasis in vivo [ 101 , 102 ]. Rictor depletion was shown to reduce AKT phosphorylation at the Ser473 and Thr308 residues and to inhibit the expression of MMP-2 and MMP-9[ 100 , 102 ].…”

“…Consistent with those findings, siRNA-mediated Rictor knockdown as well as pharmacological inhibition of mTORC2 not only led to reduced tumor cell motility, migration, and invasion in vitro [ 100 , 101 ] but also reduced melanoma liver metastasis in vivo [ 101 , 102 ]. Rictor depletion was shown to reduce AKT phosphorylation at the Ser473 and Thr308 residues and to inhibit the expression of MMP-2 and MMP-9[ 100 , 102 ]. Moreover, upon Rictor inhibition, interaction with stromal components such as hepatic stellate cells and HGF-induced melanoma cell activation/motility was impaired[ 101 ].…”

Regulation of human mTOR complexes by DEPTOR

“…Competitive binding at other substrate recognition elements, such as the TOS and RAIP motif binding sites in mTORC1 ( Yang et al, 2017 ; Tee and Proud, 2002 ; Nojima, 2003 ; Schalm et al, 2002 ; Böhm, 2021 ; Wang et al, 2007 ) or C-terminal parts of SIN1 ( Tatebe et al, 2017 ) in mTORC2, provides alternative target sites for mTOR inhibition. Recently developed small molecule mTOR inhibitors either utilize the above inhibitory mechanisms or their detailed mode of action is still unknown ( Benavides-Serrato et al, 2017 ; Benjamin et al, 2011 ; Wang et al, 2020 ; Guenzle et al, 2020 ).…”

The Challenging Melanoma Landscape: From Early Drug Discovery to Clinical Approval

“…This protocol was carried out by Seitz and collaborators, who inoculated B16-F10 cells into the spleen of syngeneic C57BL/6N mice and found that xanthohumol, a natural flavonoid, reduced hepatic tumor burden, as well as the number of hepatic metastases [196]. Similar results were found for compound JR-AB2-011, a mTORC2 specific inhibitor, using the same tumor induction protocol [197].…”