Author Information
1Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
2Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
3Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. zjuchenye@gmail.com.
4Experimental Drug Development Centre, Agency for Science, Technology and Research, Singapore, Singapore.
5National University Cancer Institute, National University Hospital, Singapore, Singapore.
6Division of Musculoskeletal Oncology, University Orthopaedics, Hand and Reconstructive Microsurgery Cluster, National University Hospital, Singapore, Singapore.
7Department of Hand and Reconstructive Microsurgery, National University Hospital, Singapore, Singapore.
8Greehey Children’s Cancer Research Institute, UT Health San Antonio, San Antonio, TX, USA.
9Department of Pathology, National University Hospital, Singapore, Singapore.
10Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
11Division of Hematology/Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
12Sussex Drug Discovery Centre, School of Life Sciences, University of Sussex, Brighton, UK.
13Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. xuliang.zju@gmail.com.
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.
PMID: 33564073 DOI: 10.1038/s41388-021-01661-4