ArticleProceedings of the National Academy of Sciences of the United States of America2020
Targeted CRISPR screening identifies PRMT5 as synthetic lethality combinatorial target with gemcitabine in pancreatic cancer cells.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers, 1 of them a synthesis that pooled it.
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Who cites it
71 citing papers in PubMed, 1 synthesis or guideline pooled it, 108 citations in OpenAlex.
- Systematic Evaluation Meta-Analysis of the Efficacy of Recombinant Human Endostatin Combined with Gemcitabine and Cisplatin in Non-Small-Cell Lung Cancer.Journal of healthcare engineering · 2022Pooled it
- Reactivation of DRP1 plays a functional role in resistance to MEK inhibition in pancreatic cancer cells.British journal of cancer · 2026Article
- Breaking barriers: nano-boosted drug delivery systems in overcoming the defenses of pancreatic cancer.Molecular cancer · 2026Review
- Targeting of CDK1 and PRMT5 as a potential therapeutic combination for non-small cell lung cancer.Histology and histopathology · 2026Article
- Review
- Reactivation of DRP1 plays a functional role in resistance to MEK inhibition in pancreatic cancer cells.bioRxiv : the preprint server for biology · 2026Article
- Targeting PRMTs Creates Vulnerability of DNA Double-Stand Break Repair Pathways, and Potentiates Chemotherapy Efficacy in TNBC.Cancer science · 2026Article
- Metabolic drivers of genome instability in cancer: mechanisms and therapeutic opportunities.Experimental hematology & oncology · 2026Review
- A synergistic interaction between PRMT5 and LSD1 inhibitors in AML.Science advances · 2026Article
- PRMT5 is Frequently Upregulated and a Potential Therapeutic Target in MTAP-deficient Malignant Peripheral Nerve Sheath Tumors.bioRxiv : the preprint server for biology · 2026Article
- Identification of HSPE1 as a new actionable cancer vulnerability leads to an innovative and effective combination therapy for pancreatic ductal adenocarcinoma.Molecular cancer · 2026Article
- Article
- PRMT5 upregulates KCNMB4 expression via histone methylation to promote paclitaxel resistance in advanced nasopharyngeal carcinoma.Cell death & disease · 2026Article
- DNA damage response inhibitors in pancreatic cancer: progress and challenges.Frontiers in oncology · 2026Review
- PRMT5 inhibition triggers functional ATM deficiency and sensitizes pancreatic cancer to CHK1 blockade.Frontiers in cell and developmental biology · 2026Article
- Protein arginine methyltransferase 5 as a novel therapeutic target in solid tumors.Genes & diseases · 2026Review
- Microcargos with Megaeffects: A Literature Review of Immunomodulatory, Diagnostic, Prognostic, and Therapeutic Dimensions of Exosomal MicroRNAs in Glioblastoma Multiforme.Cellular and molecular neurobiology · 2025Review
- CRISPR Technology in Disease Management: An Updated Review of Clinical Translation and Therapeutic Potential.Cell proliferation · 2025Article
- Targeting MAT2A synergistically induces DNA damage in osteosarcoma cells through EZH2-mediated H3K27me3 modification.Journal of orthopaedic translation · 2025Article
- Protein arginine methyltransferase 5 sustains Tip60-EP400 complex via SRSF1 in Merkel cell carcinoma.Life science alliance · 2025Article
11 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 1 country.
Funding
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most challenging cancers to treat. Due to the asymptomatic nature of the disease and lack of curative treatment modalities, the 5-y survival rate of PDAC patients is one of the lowest of any cancer type. The recurrent genetic alterations in PDAC are yet to be targeted. Therefore, identification of effective drug combinations is desperately needed. Here, we performed an in vivo CRISPR screen in an orthotopic patient-derived xenograft (PDX) model to identify gene targets whose inhibition creates synergistic tumor growth inhibition with gemcitabine (Gem), a first- or second-line chemotherapeutic agent for PDAC treatment. The approach revealed protein arginine methyltransferase gene 5 (PRMT5) as an effective druggable candidate whose inhibition creates synergistic vulnerability of PDAC cells to Gem. Genetic depletion and pharmacological inhibition indicate that loss of PRMT5 activity synergistically enhances Gem cytotoxicity due to the accumulation of excessive DNA damage. At the molecular level, we show that inhibition of PRMT5 results in RPA depletion and impaired homology-directed DNA repair (HDR) activity. The combination (Gem + PRMT5 inhibition) creates conditional lethality and synergistic reduction of PDAC tumors in vivo. The findings demonstrate that unbiased genetic screenings combined with a clinically relevant model system is a practical approach in identifying synthetic lethal drug combinations for cancer treatment.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.