ADDICTION OF SOFT-TISSUE SARCOMA CELLS TO MNK AND EIF4E

Abstract

Soft-tissue sarcomas (STSs) are a group of rare diseases that arise from connective tissues. The overall clinical outcome of patients with advanced tumors especially de-differentiated liposarcoma and uterine leiomyosarcoma remains unsatisfactory, albeit intensive treatment regimens including maximal surgical resection, radiation, and chemotherapy. As such, a better understanding of molecular features of STS might contribute to a more precise treatment. Potential therapeutic targets MAP kinase-interacting serine/threonine-protein kinase 1 and 2 (MNK1/2) are the convergence of Phosphoinositide 3-kinase (PI3K) and Mitogen-activated protein kinase (MAPK) intracellular transduction signal pathways. MNK1/2 are known for phosphorylating eukaryotic translation initiation factor 4E (eIF4E) and contribute to oncogenic translation. However, the knowledge about the carcinogenic dependence of MNK1/2 on STS and downstream targets of MNK1/2 in STS remains elusive.

In this study, we found that both expression and activity of MNK1/2 were highly elevated in STS cancer cells. Suppression of either MNK1 or MNK2 inhibited cell viability, anchorage-independent growth, and in vivo tumorigenicity of STS cells. Furthermore, we revealed a compelling susceptibility of STS cells to a novel and potent MNK inhibitor ETC-168 which strongly blocked eIF4E phosphorylation. Cellular responsiveness of STS cells to ETC-168 was in a positive correlation with that of phosphorylated ribosomal protein S6 (RPS6). Mirroring MNK1/2 depletion, ETC-168 treatment repressed expression of STS-driving oncoproteins including MCL1, E2F1, FOXM1, and WEE1. Importantly, combination of ETC-168 and MCL1 inhibitor S63845 exerted a synergistic anti-proliferative activity against STS cells. In summary, our data demonstrate that MNK1/2 and their targets maintain the aggressiveness of STS cells. Our findings warrant further clinical investigation of MNK inhibitors for STS treatment.