Related Experiment Video
Updated: Apr 17, 2026
Pooled CRISPR-Based Genetic Screens in Mammalian Cells
Published on: September 4, 2019
Genome-wide CRISPR screens identify PKMYT1 as a therapeutic target in pancreatic ductal adenocarcinoma
Simin Wang1, Yangjie Xiong1, Yuxiang Luo1
1CAS 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.
Abstract:
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.
Insights
Pancreatic cancer (PDAC) has poor survival rates. Researchers found PKMYT1 is a vulnerability, and inhibiting it slows tumor growth and may offer new pancreatic cancer treatments.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with limited effective therapies.
- Novel therapeutic targets are critical for improving outcomes in PDAC patients.
Purpose of the Study:
- To identify novel genetic vulnerabilities in PDAC.
- To investigate the therapeutic potential of targeting PKMYT1 in PDAC.
Main Methods:
- Genome-wide CRISPR screens were employed to identify genetic vulnerabilities.
- In vitro and in vivo studies assessed the effects of PKMYT1 ablation and pharmacological inhibition.
- Mechanistic studies explored PKMYT1's role in cell cycle regulation and PDAC tumorigenesis.
Main Results:
- PKMYT1 was identified as a non-mutant genetic vulnerability in PDAC, with high expression correlating with poor prognosis.
- PKMYT1 inhibition suppressed tumor growth, proliferation, and induced apoptosis in PDAC models.
- Pharmacological inhibition of PKMYT1 demonstrated efficacy and tumor regression in xenograft models without significant toxicity.
- PKMYT1 promotes PDAC tumorigenesis by regulating PLK1 expression and phosphorylation, beyond its canonical CDK1 function.
Conclusions:
- PKMYT1 is a critical dependency in PDAC, acting as an oncogene.
- Targeting PKMYT1 represents a promising therapeutic strategy for pancreatic cancer.
- TP53 and PRKDC activation influence sensitivity to PKMYT1 inhibition, suggesting potential biomarkers for patient stratification.
