Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an overall 5-year survival rate of <12% due to the lack of effective treatments. Novel treatment strategies are urgently needed. Here, PKMYT1 is identified through genome-wide CRISPR screens as a non-mutant, genetic vulnerability of PDAC. Higher PKMYT1 expression levels indicate poor prognosis in PDAC patients. PKMYT1 ablation inhibits tumor growth and proliferation in vitro and in vivo by regulating cell cycle progression and inducing apoptosis. Moreover, pharmacological inhibition of PKMYT1 shows efficacy in multiple PDAC cell models and effectively induces tumor regression without overt toxicity in PDAC cell line-derived xenograft and in more clinically relevant patient-derived xenograft models. Mechanistically, in addition to its canonical function of phosphorylating CDK1, PKMYT1 functions as an oncogene to promote PDAC tumorigenesis by regulating PLK1 expression and phosphorylation. Finally, TP53 function and PRKDC activation are shown to modulate the sensitivity to PKMYT1 inhibition. These results define PKMYT1 dependency in PDAC and identify potential therapeutic strategies for clinical translation.

中文翻译：

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全基因组 CRISPR 筛选将 PKMYT1 确定为胰腺导管腺癌的治疗靶点。


胰腺导管腺癌（PDAC）是一种毁灭性疾病，由于缺乏有效的治疗方法，总体 5 年生存率<12%。迫切需要新的治疗策略。在这里，PKMYT1 通过全基因组 CRISPR 筛选被鉴定为 PDAC 的非突变遗传漏洞。较高的 PKMYT1 表达水平表明 PDAC 患者预后较差。 PKMYT1 消除通过调节细胞周期进程和诱导细胞凋亡来抑制体外和体内肿瘤生长和增殖。此外，PKMYT1 的药理抑制在多种 PDAC 细胞模型中显示出功效，并有效诱导肿瘤消退，而在 PDAC 细胞系来源的异种移植物和临床上更相关的患者来源的异种移植物模型中没有明显的毒性。从机制上讲，除了磷酸化 CDK1 的典型功能外，PKMYT1 还作为癌基因，通过调节 PLK1 表达和磷酸化来促进 PDAC 肿瘤发生。最后，TP53 功能和 PRKDC 激活可调节对 PKMYT1 抑制的敏感性。这些结果定义了 PDAC 中的 PKMYT1 依赖性，并确定了临床转化的潜在治疗策略。