Selective mTORC2 Inhibitor Therapeutically Blocks Breast Cancer Cell Growth and Survival

Abstract

Small-molecule inhibitors of the mTORC2 kinase (torkinibs) have shown efficacy in early clinical trials. However, the torkinibs under study also inhibit the other mTOR-containing complex mTORC1. While mTORC1/mTORC2 combined inhibition may be beneficial in cancer cells, recent reports describe compensatory cell survival upon mTORC1 inhibition due to loss of negative feedback on PI3K, increased autophagy, and increased macropinocytosis. Genetic models suggest that selective mTORC2 inhibition would be effective in breast cancers, but the lack of selective small-molecule inhibitors of mTORC2 have precluded testing of this hypothesis to date. Here we report the engineering of a nanoparticle-based RNAi therapeutic that can effectively silence the mTORC2 obligate cofactor Rictor. Nanoparticle-based Rictor ablation in HER2-amplified breast tumors was achieved following intratumoral and intravenous delivery, decreasing Akt phosphorylation and increasing tumor cell killing. Selective mTORC2 inhibition , combined with the HER2 inhibitor lapatinib, decreased the growth of HER2-amplified breast cancers to a greater extent than either agent alone, suggesting that mTORC2 promotes lapatinib resistance, but is overcome by mTORC2 inhibition. Importantly, selective mTORC2 inhibition was effective in a triple-negative breast cancer (TNBC) model, decreasing Akt phosphorylation and tumor growth, consistent with our findings that RICTOR mRNA correlates with worse outcome in patients with basal-like TNBC. Together, our results offer preclinical validation of a novel RNAi delivery platform for therapeutic gene ablation in breast cancer, and they show that mTORC2-selective targeting is feasible and efficacious in this disease setting. This study describes a nanomedicine to effectively inhibit the growth regulatory kinase mTORC2 in a preclinical model of breast cancer, targeting an important pathogenic enzyme in that setting that has been undruggable to date. .

mTORC2 deficiency in cutaneous dendritic cells potentiates CD8+ effector T cell responses and accelerates skin graft rejection

“…[10][11][12][13] Indeed, the development of glucose intolerance and insulin resistance in transplant patients receiving rapamycin may be mediated by mTORC2 inhibition. 14,15 However, although selective mTORC2 targeting has been shown recently to block tumor growth in mice, 16,17 we are not aware of any reports of selective mTORC2 targeting in graft donors or recipients. 14,15 However, although selective mTORC2 targeting has been shown recently to block tumor growth in mice, 16,17 we are not aware of any reports of selective mTORC2 targeting in graft donors or recipients.…”

“…11 In mice, dual inhibition of mTORC1 and mTORC2 using novel adenosine triphosphase (ATP) competitive inhibitors is less effective in prolonging heart allograft survival than is immune suppression with rapamycin alone. 14,15 However, although selective mTORC2 targeting has been shown recently to block tumor growth in mice, 16,17 we are not aware of any reports of selective mTORC2 targeting in graft donors or recipients.…”

“…should be considered in interpreting the influence of mTOR inhibitors on immune reactivity and in the development of new-generation dual mTORC1 and mTORC2 inhibitors 14 and selective mTORC2 inhibitors 16,17. ACK N OWLED G M ENTSThis work was supported by NIH grants R01 AI67541 and R01 AI1188777 (to AWT) and by research funds provided by the Starzl Transplantation Institute.…”

Dynamic Modeling of Signal Transduction by mTOR Complexes in Cancer

“…It has been shown that selective or targeted mTORC2 inhibition causes reduced cell proliferation, tumor size, and angiogenesis in several types of cancers including colon cancer, breast cancer and multiple myeloma [49][50][51][52][53]. Differential effects of dose-interval schedules of rapamycin (or rapalogs) on colon cancer have also been investigated.…”

The role of RICTOR amplification in targeted therapy and drug resistance

“…Thomas et al (2018) developed a nanoparticle-based RNAi therapeutic that could effectively silence the mTORC2 cofactor RICTOR. By intratumoral or intravenous delivery, nanomedicine in combination with lapatinib impaired the survival of HER2-amplified breast cancer cells (Werfel et al 2018).…”