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

  • Oncogene. 2021 Mar;40(10):1851-1867. doi: 10.1038/s41388-021-01661-4.
Xin-Yu Ke  1  2 ,  Ye Chen  3 ,  Valarie Yu-Yan Tham  1 ,  Ruby Yu-Tong Lin  1 ,  Pushkar Dakle  1 ,  Kassoum Nacro  4 ,  Mark Edward Puhaindran  5  6  7 ,  Peter Houghton  8 ,  Angela Pang  5 ,  Victor Kwanmin Lee  9 ,  Ling-Wen Ding  10 ,  Sigal Gery  11 ,  Jeffrey Hill  12 ,  Leilei Chen  1  2 ,  Liang Xu  13 ,  H Phillip Koeffler  1  5  11
Affiliations
  • 1. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • 2. Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 3. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. [email protected].
  • 4. Experimental Drug Development Centre, Agency for Science, Technology and Research, Singapore, Singapore.
  • 5. National University Cancer Institute, National University Hospital, Singapore, Singapore.
  • 6. Division of Musculoskeletal Oncology, University Orthopaedics, Hand and Reconstructive Microsurgery Cluster, National University Hospital, Singapore, Singapore.
  • 7. Department of Hand and Reconstructive Microsurgery, National University Hospital, Singapore, Singapore.
  • 8. Greehey Children's Cancer Research Institute, UT Health San Antonio, San Antonio, TX, USA.
  • 9. Department of Pathology, National University Hospital, Singapore, Singapore.
  • 10. Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
  • 11. Division of Hematology/Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
  • 12. Sussex Drug Discovery Centre, School of Life Sciences, University of Sussex, Brighton, UK.
  • 13. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. [email protected].
PMID: 33564073 DOI: 10.1038/s41388-021-01661-4
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.

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