Although gemcitabine is the cornerstone of care for pancreatic ductal adenocarcinoma (PDA), patients lack durable responses and relapse is inevitable. While the underlying mechanisms leading to gemcitabine resistance are likely to be multifactorial, there is a strong association between activating gemcitabine metabolism pathways and clinical outcome. This study evaluated casein kinase 1 delta (CK1δ) as a potential therapeutic target for PDA and bladder cancer, in which CK1δ is frequently overexpressed. We assessed the antitumor effects of genetically silencing or pharmacologically inhibiting CK1δ using our in-house CK1δ small-molecule inhibitor SR-3029, either alone or in combination with gemcitabine, on the proliferation and survival of pancreatic and bladder cancer cell lines and orthotopic mouse models. Genetic studies confirmed that silencing CK1δ or treatment with SR-3029 induced a significant upregulation of deoxycytidine kinase (dCK), a rate-limiting enzyme in gemcitabine metabolite activation. The combination of SR-3029 with gemcitabine induced synergistic antiproliferative activity and enhanced apoptosis in both pancreatic and bladder cancer cells. Furthermore, in an orthotopic pancreatic tumor model, we observed improved efficacy with combination treatment concomitant with increased dCK expression. This study demonstrates that CK1δ plays a role in gemcitabine metabolism, and that the combination of CK1δ inhibition with gemcitabine holds promise as a future therapeutic option for metastatic PDA as well as other cancers with upregulated CK1δ expression.

中文翻译：

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靶向酪蛋白激酶 1 δ 通过上调脱氧胞苷激酶使胰腺癌细胞和膀胱癌细胞对吉西他滨治疗敏感


尽管吉西他滨是胰腺导管腺癌 (PDA) 治疗的基石，但患者缺乏持久的反应，复发是不可避免的。虽然导致吉西他滨耐药的潜在机制可能是多因素的，但激活吉西他滨代谢途径与临床结果之间存在密切关联。这项研究评估了酪蛋白激酶 1 δ (CK1δ) 作为 PDA 和膀胱癌的潜在治疗靶点，其中 CK1δ 经常过度表达。我们使用我们的内部 CK1δ 小分子抑制剂 SR-3029 单独或与吉西他滨联合评估了基因沉默或药理学抑制 CK1δ 对胰腺癌细胞系和膀胱癌细胞系以及原位小鼠模型的增殖和存活的抗肿瘤作用。遗传学研究证实，沉默 CK1δ 或用 SR-3029 治疗可诱导脱氧胞苷激酶 (dCK) 显着上调，dCK 是吉西他滨代谢物激活的限速酶。 SR-3029 与吉西他滨的组合可诱导胰腺癌细胞和膀胱癌细胞的协同抗增殖活性并增强细胞凋亡。此外，在原位胰腺肿瘤模型中，我们观察到联合治疗的疗效随着 dCK 表达的增加而提高。这项研究表明，CK1δ 在吉西他滨代谢中发挥作用，并且 CK1δ 抑制与吉西他滨的组合有望成为转移性 PDA 以及其他 CK1δ 表达上调的癌症的未来治疗选择。