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

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Enhanced DNA repair mechanisms contribute to resistance against DNA-targeted therapies, such as poly ADP ribose polymerase (PARP) inhibitors.
• Spleen associated tyrosine kinase (Syk) is a non-receptor tyrosine kinase involved in various cellular processes, including immune responses and development.

Purpose of the Study:

• To investigate the role of Syk in DNA double-strand break repair and its contribution to therapeutic resistance in cancer.
• To elucidate the molecular pathway through which Syk influences DNA repair and homologous recombination (HR).

Main Methods:

• Assessing Syk expression in high-grade serous ovarian cancer and triple-negative breast cancer cell lines.
• Investigating the activation and recruitment of Syk to DNA double-strand breaks using techniques like Western blotting and immunofluorescence.
• Evaluating the effect of Syk inhibition or genetic deletion on DNA repair, HR, and therapeutic response.

Main Results:

• Syk expression in ovarian and breast cancers promotes DNA double-strand break resection and homologous recombination (HR).
• ATM activates Syk following DNA damage, and NBS1 recruits Syk to break sites, where it phosphorylates CtIP at Thr-847, enhancing repair.
• Inhibition or deletion of Syk impairs CtIP phosphorylation and overcomes resistance to DNA-targeted therapies.

Conclusions:

• Syk promotes therapeutic resistance by enhancing DNA resection and HR via a novel ATM-Syk-CtIP pathway.
• Targeting Syk represents a promising strategy to sensitize Syk-expressing tumors to PARP inhibitors, radiation, and other DNA-targeted therapies.