Syk-dependent homologous recombination activation promotes cancer resistance to DNA targeted therapy
Enhanced DNA repair is an important mechanism of inherent and acquired resistance to DNA targeted therapies, including poly ADP ribose polymerase (PARP) inhibition. Spleen associated tyrosine kinase (Syk) is a non-receptor tyrosine kinase acknowledged for its regulatory roles in immune cell function, cell adhesion, and vascular development. This study presents evidence indicating that Syk expression in high-grade serous ovarian cancer and triple-negative breast cancers promotes DNA double-strand break resection, homologous recombination (HR), and subsequent therapeutic resistance. Our investigations reveal that Syk is activated by ATM following DNA damage and is recruited to DNA double-strand breaks by NBS1. Once localized to the break site, Syk phosphorylates CtIP, a pivotal mediator of resection and HR, at Thr-847 to promote repair activity, particularly in Syk-expressing cancer cells. Inhibition of Syk or its genetic deletion impedes CtIP Thr-847 phosphorylation and overcomes the resistant phenotype. Collectively, our findings suggest a model wherein Syk fosters therapeutic resistance by promoting DNA resection and HR through a hitherto uncharacterized ATM-Syk-CtIP pathway. Moreover, Syk emerges as a promising tumor-specific target to sensitize Syk-expressing tumors to PARP inhibitors, radiation and other DNA-targeted therapies.
Journal
Drug Resistance UpdatesAuthors
Funding
Mayo Clinic Building Interdisciplinary Research Careers in Women’s HealthMSTP at Mayo Clinic RochesterBiostatistic and Patient Registry CoreSensitizing Ovarian Cancer To PARP inhibitor and platinum treatmentCancer Risk Assessment, Early Detection, and Interception Research ProgramProject 2: Next Generation TOP1 Inhibition for the Treatment of Ovarian CancerNICHD FundingMayo Clinic Grant HD065987Biostatistic and Patient Registry CoreCancer Risk Assessment, Early Detection, and Interception Research ProgramProject 2: Next Generation TOP1 Inhibition for the Treatment of Ovarian CancerAmerican Society for Radiation Oncology FundingProject 2: Next Generation TOP1 Inhibition for the Treatment of Ovarian CancerBiostatistic and Patient Registry CoreCancer Risk Assessment, Early Detection, and Interception Research ProgramSensitizing Ovarian Cancer To PARP inhibitor and platinum treatment