General Information
- Project ID
- OEP004116
- Project Name
- Genome-wide CRISPR screens identify PKMYT1 as a therapeutic target in pancreatic ductal adenocarcinoma
- Description
- Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an overall 5-year survival rate of <12% due to the lack of effective treatments. KRAS G12C and mutant-BRAC targeted therapies are actively investigated in PDAC patients. Unfortunately, only a small subgroup of patients harbors these mutants. Novel treatment strategies are urgently needed. Here, we identified through genome-wide CRISPR screens that PKMYT1 is a non-mutant, genetic vulnerability of PDAC, but not a pan-essential depending on TP53 mutation status. 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 functions of phosphorylating CDK1, proteomic screens demonstrate that PKMYT1 interacts with PLK1 and PRKDC in PDAC. PKMYT1 inhibition regulates PLK1 and PRKDC expression and activation, respectively, to maximize treatment effects for PDAC. These results define PKMYT1 dependency in PDAC and identify potential therapeutic strategies for clinical translation.
Project information
- Experiments
- 2
- Samples
- 6
Sample ID Sample Name Sample Subject Type Organism Tissue Create Date OES306036 Pa-Tu-8988T.PD0 Cell line Homo sapiens cell line 2023-04-22 OES306037 Pa-Tu-8988T.PD14 Cell line Homo sapiens cell line 2023-04-22 OES306038 YAPC.PD0 Cell line Homo sapiens cell line 2023-04-22 OES306039 YAPC.PD14 Cell line Homo sapiens cell line 2023-04-22 OES306040 YAPC_EV Cell line Homo sapiens cell line 2023-04-22 OES306041 YAPC_PKMYT1-3 Cell line Homo sapiens cell line 2023-04-22 - Runs
-
10
Run ID Run Name Experiment Sample Data Num Create Date OER394698 YAPC_EV_1.fq.gz OEX023088 OES306040 1 2023-04-25 OER394699 YAPC_PKMYT1.3_1.fq.gz OEX023088 OES306041 1 2023-04-25 OER394700 Pa.Tu.8988T.PD14_R2.fastq.gz OEX023089 OES306037 1 2023-04-25 OER394701 Pa.Tu.8988T.PD0_R1.fastq.gz OEX023089 OES306036 1 2023-04-25 OER394702 Pa.Tu.8988T.PD0_R2.fastq.gz OEX023089 OES306036 1 2023-04-25 OER394703 YAPC.PD0_R1.fastq.gz OEX023089 OES306038 1 2023-04-25 OER394704 YAPC.PD0_R2.fastq.gz OEX023089 OES306038 1 2023-04-25 OER394705 YAPC.PD14_R1.fastq.gz OEX023089 OES306039 1 2023-04-25 OER394706 YAPC.PD14_R2.fastq.gz OEX023089 OES306039 1 2023-04-25 OER394707 Pa.Tu.8988T.PD14_R1.fastq.gz OEX023089 OES306037 1 2023-04-25
Author Information
- Create Date
- 2023-04-21
- Last Modified
- 2023-04-25
- Submission
- Yuexiang Wang
- Shanghai Institute of Nutrition and Health