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Tytuł pozycji:

Targeted CRISPR screening identifies PRMT5 as synthetic lethality combinatorial target with gemcitabine in pancreatic cancer cells.

Tytuł:
Targeted CRISPR screening identifies PRMT5 as synthetic lethality combinatorial target with gemcitabine in pancreatic cancer cells.
Autorzy:
Wei X; Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22903.
Yang J; Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22903.
Adair SJ; Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA 22903.
Ozturk H; Feinberg School of Medicine, Robert Lurie Comprehensive Cancer Center, Department of Obstetrics and Gynecology, The Northwestern University, Chicago, IL 60611.
Kuscu C; Transplant Research Institute, University of Tennessee Health Science Center, Memphis, TN 38163.
Lee KY; Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22903.
Kane WJ; Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA 22903.
O'Hara PE; Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA 22903.
Liu D; Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA 22903.
Demirlenk YM; Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22903.
Habieb AH; Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22903.
Yilmaz E; Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22903.
Dutta A; Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22903.
Bauer TW; Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA 22903.
Adli M; Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22903; .; Feinberg School of Medicine, Robert Lurie Comprehensive Cancer Center, Department of Obstetrics and Gynecology, The Northwestern University, Chicago, IL 60611.
Źródło:
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Nov 10; Vol. 117 (45), pp. 28068-28079. Date of Electronic Publication: 2020 Oct 23.
Typ publikacji:
Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Język:
English
Imprint Name(s):
Original Publication: Washington, DC : National Academy of Sciences
MeSH Terms:
Protein-Arginine N-Methyltransferases*/antagonists & inhibitors
Protein-Arginine N-Methyltransferases*/genetics
Protein-Arginine N-Methyltransferases*/metabolism
Antineoplastic Agents/*pharmacology
Deoxycytidine/*analogs & derivatives
Pancreatic Neoplasms/*metabolism
Animals ; CRISPR-Cas Systems/genetics ; Cell Line, Tumor ; Cell Survival/drug effects ; Deoxycytidine/pharmacology ; Drug Development ; Gene Knockout Techniques ; Humans ; Mice, Nude ; Xenograft Model Antitumor Assays ; Gemcitabine
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Grant Information:
R01 CA060499 United States CA NCI NIH HHS; L30 CA124093 United States CA NCI NIH HHS; P30 CA044579 United States CA NCI NIH HHS; R25 CA206972 United States CA NCI NIH HHS; R01 CA211648 United States CA NCI NIH HHS
Contributed Indexing:
Keywords: CRISPR screening; cancer genomics and epigenomics; combinatorial drugs targets; pancreatic cancer; synthetic lethality
Substance Nomenclature:
0 (Antineoplastic Agents)
0W860991D6 (Deoxycytidine)
EC 2.1.1.319 (PRMT5 protein, human)
EC 2.1.1.319 (Protein-Arginine N-Methyltransferases)
0 (Gemcitabine)
Entry Date(s):
Date Created: 20201024 Date Completed: 20210104 Latest Revision: 20221207
Update Code:
20240105
PubMed Central ID:
PMC7668168
DOI:
10.1073/pnas.2009899117
PMID:
33097661
Czasopismo naukowe
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.
Competing Interests: The authors declare no competing interest.

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