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Syk-dependent alternative homologous recombination activation promotes cancer resistance to DNA targeted therapy

Qin Zhou1, Xinyi Tu1, Xiaonan Hou2

  • 1Department of Radiation Oncology, Mayo Clinic.

Research Square
|June 19, 2023
PubMed

Insights

Spleen associated tyrosine kinase (Syk) promotes cancer resistance to DNA targeted therapies by enhancing DNA repair. Inhibiting Syk may sensitize tumors to treatments like PARPi.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Enhanced DNA repair confers resistance to DNA-targeted therapies, including poly ADP ribose polymerase (PARPi) inhibitors.
  • Spleen associated tyrosine kinase (Syk), a non-receptor tyrosine kinase, is implicated in immune cell function and vascular development.
  • Syk expression is observed in high-grade serous ovarian cancer and triple-negative breast cancers.

Approach:

  • Investigated the role of Syk in DNA double-strand break (DSB) repair and therapeutic resistance.
  • Examined Syk activation by ATM and recruitment to DSBs by NBS1.
  • Assessed the impact of Syk inhibition or genetic deletion on CtIP phosphorylation and homologous recombination (HR).

Key Points:

  • Syk promotes DNA double-strand break resection and homologous recombination (HR) in cancer cells.
  • ATM activates Syk following DNA damage, and NBS1 recruits Syk to DSBs.
  • Syk phosphorylates CtIP at Thr-847, enhancing DNA repair and conferring therapeutic resistance.
  • Syk inhibition or deletion abrogates CtIP phosphorylation and overcomes resistance.

Conclusions:

  • Syk drives therapeutic resistance by promoting DNA resection and HR via a novel ATM-Syk-CtIP pathway.
  • Syk is a potential tumor-specific target to sensitize Syk-expressing cancers to PARPi and other DNA-targeted therapies.

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