Dual mTOR inhibitor MLN0128 suppresses Merkel cell carcinoma (MCC) xenograft tumor growth

Abstract

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer. Pathologic activation of PI3K/mTOR pathway and elevated expression of c-Myc are frequently detected in MCC. Yet, there is no targeted therapy presently available for this lethal disease. Recently, MLN0128, a second-generation dual TORC1/2 inhibitor is shown to have therapeutic efficacy in preclinical studies. MLN0128 is currently in clinical trials as a potential therapy for advanced cancers. Here we characterize the therapeutic efficacy of MLN0128 in the preclinical setting of MCC and delineate downstream targets of mTORC1/2 in MCC cellular systems. MLN0128 significantly attenuates xenograft MCC tumor growth independent of Merkel cell polyomavirus. Moreover, MLN0128 markedly diminishes MCC cell proliferation and induces apoptosis. Further investigations indicate that senescence does not contribute to MLN0128-mediated repression of xenograft MCC tumor growth. Finally, we also observe robust antitumor effects of MLN0128 when administered as a dual therapy with JQ1, a bromodomain protein BRD4 inhibitor. These results suggest dual blockade of PI3K/mTOR pathway and c-Myc axis is effective in the control of MCC tumor growth. Our results demonstrate that MLN0128 is potent as monotherapy or as a member of combination therapy with JQ1 for advanced MCC.

Identification and activation of TLR4-mediated signalling pathways by alginate-derived guluronate oligosaccharide in RAW264.7 macrophages

“…Combined with our previous findings that the upregulation of phosphorylated IκB induced by GOS is associated with NF-κB nuclear translocation 20 , we speculated that Akt phosphorylation contributes to GOS-stimulated signalling. In addition, the Akt/mTOR signalling pathway is reported to participate in various processes, including cell growth, autophagy, apoptosis and immune regulation 27 , and activated Akt was found to induce expression of IL-6, TNF-α and IL-12 by initiating phosphorylation of mTOR and p70 S6K 28 . According to current findings (Figs 2D,E and 3), we propose that GOS-mediated immune regulation in RAW264.7 macrophages is divided into the following major steps: (1) GOS the surface receptor TLR4; (2) PI3K is activated by TLR4 and subsequently induces Akt phosphorylation; (3) phosphorylated Akt triggers IκB phosphorylation, resulting in (4) the release and translocation of NF-κB into the nucleus; (5) mTOR and p70 S6K are also activated by p-Akt; (6) all these factors work together or separately to induce the production of inflammatory mediators.…”

Merkel Cell Carcinoma Therapeutic Update

“…Specifically targeting both mTOR complex 1 and complex 2, the dual mTOR inhibitor, MLN0128, was able to inhibit MCC xenograft tumor growth in vivo [75]. A phase I dose escalation protocol of MLN0128 is expected to complete imminently [76], and a phase II trial for patients with advanced MCC has just begun recruiting patients [77].…”

Synergistic cytotoxicity of BIIB021 with triptolide through suppression of PI3K/Akt/mTOR and NF-κB signal pathways in thyroid carcinoma cells

“…Meanwhile, BIIB021 results in death of chronic myeloid leukemia cells through regulation of mTOR-Ulk1 signal pathway [23]. In regard to involvement of mTOR in cell survival, it was reported that the dual mTOR inhibitor MLN0128 inhibited tumor growth in Merkel cell carcinoma-xenograft model [29]. In this study, BIIB021 reduced expression of total and phospho-Akt, denoting the impediment of phosphorylation as well as expression of Akt by BIIB021.…”