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Identification of a Novel SYK/c-MYC/MALAT1 Signaling Pathway and Its Potential Therapeutic Value in Ewing Sarcoma

Haibo Sun1,2, De-Chen Lin3, Qi Cao2

  • 1Immunogenetics and Transplantation Laboratory, Department of Surgery, University of California San Francisco, San Francisco, California. Haibo.Sun@ucsf.edu De-chen.Lin@cshs.org.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|March 25, 2017
PubMed

Insights

Spleen tyrosine kinase (SYK) is a promising therapeutic target for Ewing sarcoma (EWS). Inhibiting SYK, along with c-MYC and MALAT1, shows significant potential for treating this rare cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Ewing sarcoma (EWS) is a rare and aggressive cancer primarily affecting young individuals.
  • Tyrosine kinases (TKs) are frequently activated in cancers, presenting potential therapeutic targets.
  • Understanding signaling pathways in EWS is crucial for developing effective treatments.

Purpose of the Study:

  • To identify actionable therapeutic targets in Ewing sarcoma using high-throughput screening.
  • To investigate the role of Spleen tyrosine kinase (SYK) in EWS pathogenesis.
  • To elucidate the signaling pathway involving SYK, c-MYC, and MALAT1 in EWS.

Main Methods:

  • Conducted siRNA and small-molecule inhibitor screens to identify candidate targets in EWS cells.
  • Assessed SYK phosphorylation in EWS patient samples and cell lines.
  • Utilized genetic and pharmacological inhibition of SYK, followed by pathway analysis (cDNA microarrays) and investigation of MALAT1 regulation (ChIP-qPCR, luciferase reporter, qRT-PCR).

Main Results:

  • SYK was identified as a druggable target in both screens and was highly phosphorylated in most EWS cells.
  • SYK inhibition significantly reduced EWS cell proliferation both in vitro and in vivo.
  • A novel signaling axis, SYK/c-MYC/MALAT1, was identified, where SYK activates c-MYC, which then transcriptionally upregulates MALAT1, promoting EWS cell proliferation.

Conclusions:

  • The SYK/c-MYC/MALAT1 signaling pathway represents a novel and promising therapeutic target for Ewing sarcoma.
  • Targeting SYK offers a potential strategy to inhibit EWS growth and proliferation.
  • Further research into this pathway could lead to the development of new EWS treatments.

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