MNK1 and MNK2 enforce expression of E2F1, FOXM1, and WEE1 to drive soft tissue sarcoma

Abstract

Soft tissue sarcoma (STS) is a heterogeneous disease that arises from connective tissues. Clinical outcome of patients with advanced tumors especially de-differentiated liposarcoma and uterine leiomyosarcoma remains unsatisfactory, despite intensive treatment regimens including maximal surgical resection, radiation, and chemotherapy. MAP kinase-interacting serine/threonine-protein kinase 1 and 2 (MNK1/2) have been shown to contribute to oncogenic translation via phosphorylation of eukaryotic translation initiation factor 4E (eIF4E). However, little is known about the role of MNK1/2 and their downstream targets in STS. In this study, we show that depletion of either MNK1 or MNK2 suppresses cell viability, anchorage-independent growth, and tumorigenicity of STS cells. We also identify a compelling antiproliferative efficacy of a novel, selective MNK inhibitor ETC-168. Cellular responsiveness of STS cells to ETC-168 correlates positively with that of phosphorylated ribosomal protein S6 (RPS6). Mirroring MNK1/2 silencing, ETC-168 treatment strongly blocks eIF4E phosphorylation and represses expression of sarcoma-driving onco-proteins including E2F1, FOXM1, and WEE1. Moreover, combination of ETC-168 and MCL1 inhibitor S63845 exerts a synergistic antiproliferative activity against STS cells. In summary, our study reveals crucial roles of MNK1/2 and their downstream targets in STS tumorigenesis. Our data encourage further clinical translation of MNK inhibitors for STS treatment.

Inhibition MNK‐eIF4E‐β‐catenin preferentially sensitizes gastric cancer to chemotherapy

“…The analysis of IC 50 for MNK inhibitors on gastric cancer cell lines demonstrated that tomivosertib is most potent, followed by BAY 1143269 and CGP 57380 (Table 1). The cellular ID 50 of these MNK inhibitors is also consistent with their biochemical IC 50 [19, 20], and we therefore focused on tomivosertib in the following studies.…”

Overcoming Paradoxical Kinase Priming by a Novel MNK1 Inhibitor

“…Previous reports indicate that MNK1 degradation by VNLG-152R but not inhibition of the kinase activity by eFT508 caused a reduced number of viable MDA-MB-231 cells in vitro . In line with this, knock-down of MNK1 has been reported to affect cell growth in different cancer cell line models in vitro . , We therefore compared cell growth inhibition between the eFT508 and EB1 . In line with the above results, EB1 treatment caused a dose-dependent growth defect in MDA-MB-231 with a maximal reduction to 60% at 20 μM (Figure E).…”

“… 51 In line with this, knock-down of MNK1 has been reported to affect cell growth in different cancer cell line models in vitro . 49 , 50 We therefore compared cell growth inhibition between the eFT508 and EB1 . In line with the above results, EB1 treatment caused a dose-dependent growth defect in MDA-MB-231 with a maximal reduction to 60% at 20 μM ( Figure 6 E).…”

“…Previous studies in MEFs obtained from the MNK1/2 knock-out mice have revealed that the function of those kinases is not required for normal cell growth . In contrast, various studies have reported the requirement for phosphorylation of eIF4E by MNKs for tumor cell growth in vitro and in vivo . − To test for drug selectivity, we therefore used fibroblast (IMR90) and breast cancer cell lines (MDA-MB-231, MDA-MB-468, and MCF7) as models for normal and transformed cells, respectively, and analyzed cell growth after the treatment with EB1 . As shown in Figure C, cell growth was not affected in IMR90 cells up to 20 μM and only a slight but not significant effect could be observed at higher concentrations.…”

“…Supporting this, many other protein kinases, including the MNK upstream kinases ERK and p38, have been reported to carry out additional functions such as scaffolding. 55 Moreover, genetic ablation of MNK1, in which both structural and catalytic activities are impaired, has been reported to block tumor cell growth 49 , 50 and only the novel MNK inhibitor EB1 is able to phenocopy this.…”