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.

中文翻译：

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Syk 依赖性同源重组激活促进癌症对 DNA 靶向治疗的耐药性


增强的 DNA 修复是对 DNA 靶向治疗（包括多聚 ADP 核糖聚合酶 （PARP） 抑制）的固有和获得性耐药的重要机制。脾相关酪氨酸激酶 （Syk） 是一种非受体酪氨酸激酶，因其在免疫细胞功能、细胞粘附和血管发育中的调节作用而得到认可。本研究提供的证据表明，Syk 在高级别浆液性卵巢癌和三阴性乳腺癌中的表达促进了 DNA 双链断裂切除、同源重组 （HR） 和随后的治疗耐药性。我们的调查显示，Syk 在 DNA 损伤后被 ATM 激活，并被 NBS1 募集到 DNA 双链断裂中。一旦定位到断裂位点，Syk 就会在 Thr-847 位点磷酸化 CtIP（切除和 HR 的关键介质），以促进修复活性，尤其是在表达 Syk 的癌细胞中。抑制 Syk 或其基因缺失会阻碍 CtIP Thr-847 磷酸化并克服耐药表型。总的来说，我们的研究结果表明一种模型，其中 Syk 通过迄今为止未表征的 ATM-Syk-CtIP 通路促进 DNA 切除和 HR 来促进治疗耐药性。此外，Syk 已成为一种有前途的肿瘤特异性靶点，可使表达 Syk 的肿瘤对 PARP 抑制剂、放疗和其他 DNA 靶向疗法敏感。