CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 200031, Shanghai, China.
Department of Pathology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 200127, Shanghai, China.
EMBO Mol Med. 2024 May;16(5):1115-1142. doi: 10.1038/s44321-024-00060-y. Epub 2024 Apr 3.
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.
胰腺导管腺癌（PDAC）是一种毁灭性疾病，由于缺乏有效治疗方法，总体 5 年生存率<12%。迫切需要新的治疗策略。在这里，通过全基因组 CRISPR 筛选鉴定出 PKMYT1 是 PDAC 的一种非突变、遗传易感性。较高的 PKMYT1 表达水平表明 PDAC 患者预后不良。PKMYT1 缺失通过调节细胞周期进程和诱导细胞凋亡，在体外和体内均能抑制肿瘤生长和增殖。此外，PKMYT1 的药理学抑制在多种 PDAC 细胞模型中均有效，并能有效地诱导肿瘤消退，而在 PDAC 细胞系衍生的异种移植和更具临床相关性的患者衍生异种移植模型中无明显毒性。从机制上讲，除了其磷酸化 CDK1 的典型功能外，PKMYT1 还作为一种癌基因，通过调节 PLK1 的表达和磷酸化来促进 PDAC 的肿瘤发生。最后，TP53 功能和 PRKDC 激活被证明可调节对 PKMYT1 抑制的敏感性。这些结果定义了 PDAC 中对 PKMYT1 的依赖性，并确定了潜在的临床转化治疗策略。
