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

• Published in: Drug resistance updates 2024-05, Vol.74, p.101085, Article 101085
• Main Authors: Zhou, Qin, Tu, Xinyi, Hou, Xiaonan, Yu, Jia, Zhao, Fei, Huang, Jinzhou, Kloeber, Jake, Olson, Anna, Gao, Ming, Luo, Kuntian, Zhu, Shouhai, Wu, Zheming, Zhang, Yong, Sun, Chenyu, Zeng, Xiangyu, Schoolmeester, Kenneth J., Weroha, John S., Hu, Xiwen, Jiang, Yanxia, Wang, Liewei, Mutter, Robert W., Lou, Zhenkun
• Format: Article
• Language: English
• Subjects: Animals; Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors; Ataxia Telangiectasia Mutated Proteins - genetics; Ataxia Telangiectasia Mutated Proteins - metabolism; Cancer resistance; Cell Line, Tumor; CtIP; DNA Breaks, Double-Stranded - drug effects; DNA Damage - drug effects; DNA Repair - drug effects; DNA targeted therapy; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Female; Homologous Recombination; Humans; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Phosphorylation; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Syk; Syk Kinase - antagonists & inhibitors; Syk Kinase - genetics; Syk Kinase - metabolism; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology
• ISSN: 1368-7646; 1532-2084; 1532-2084
• DOI: 10.1016/j.drup.2024.101085

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.