{"doi":"10.1186/1479-5876-7-43","title":"Synthetic lethal RNAi screening identifies sensitizing targets for gemcitabine therapy in pancreatic cancer","abstract":null,"journal":"Journal of Translational Medicine","year":2009,"id":588663,"datarank":4.31154963449176,"base_score":4.6913478822291435,"endowment":4.6913478822291435,"self_citation_contribution":0.7037021823343717,"citation_network_contribution":3.6078474521573884,"self_endowment_contribution":0.7037021823343717,"citer_contribution":3.6078474521573884,"corpus_percentile":null,"corpus_rank":null,"citation_count":108,"citer_count":87,"citers_with_citation_signal":70,"citers_with_endowment":70,"datacite_reuse_total":2,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1506011,"name":"Irma M Gonzales","orcid":null,"position":1,"is_corresponding":false},{"id":1506012,"name":"Gargi D Basu","orcid":null,"position":2,"is_corresponding":false},{"id":1506013,"name":"Ashish Choudhary","orcid":null,"position":3,"is_corresponding":false},{"id":1506014,"name":"Shilpi Arora","orcid":null,"position":4,"is_corresponding":false},{"id":1506015,"name":"Kristen M Bisanz","orcid":null,"position":5,"is_corresponding":false},{"id":1506016,"name":"Jeffrey A Kiefer","orcid":null,"position":6,"is_corresponding":false},{"id":1506017,"name":"Meredith C Henderson","orcid":null,"position":7,"is_corresponding":false},{"id":1506018,"name":"Jeffrey M Trent","orcid":null,"position":8,"is_corresponding":false},{"id":1230698,"name":"Daniel D Von Hoff","orcid":null,"position":9,"is_corresponding":false},{"id":1506019,"name":"Spyro Mousses","orcid":null,"position":10,"is_corresponding":false},{"id":1506010,"name":"David O Azorsa","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Synthetic lethal RNAi screening identifies sensitizing targets for gemcitabine therapy in pancreatic cancer","abstract":"BACKGROUND: Pancreatic cancer retains a poor prognosis among the gastrointestinal cancers. It affects 230,000 individuals worldwide, has a very high mortality rate, and remains one of the most challenging malignancies to treat successfully. Treatment with gemcitabine, the most widely used chemotherapeutic against pancreatic cancer, is not curative and resistance may occur. Combinations of gemcitabine with other chemotherapeutic drugs or biological agents have resulted in limited improvement. METHODS: In order to improve gemcitabine response in pancreatic cancer cells, we utilized a synthetic lethal RNAi screen targeting 572 known kinases to identify genes that when silenced would sensitize pancreatic cancer cells to gemcitabine. RESULTS: Results from the RNAi screens identified several genes that, when silenced, potentiated the growth inhibitory effects of gemcitabine in pancreatic cancer cells. The greatest potentiation was shown by siRNA targeting checkpoint kinase 1 (CHK1). Validation of the screening results was performed in MIA PaCa-2 and BxPC3 pancreatic cancer cells by examining the dose response of gemcitabine treatment in the presence of either CHK1 or CHK2 siRNA. These results showed a three to ten-fold decrease in the EC50 for CHK1 siRNA-treated cells versus control siRNA-treated cells while treatment with CHK2 siRNA resulted in no change compared to controls. CHK1 was further targeted with specific small molecule inhibitors SB 218078 and PD 407824 in combination with gemcitabine. Results showed that treatment of MIA PaCa-2 cells with either of the CHK1 inhibitors SB 218078 or PD 407824 led to sensitization of the pancreatic cancer cells to gemcitabine. CONCLUSION: These findings demonstrate the effectiveness of synthetic lethal RNAi screening as a tool for identifying sensitizing targets to chemotherapeutic agents. These results also indicate that CHK1 could serve as a putative therapeutic target for sensitizing pancreatic cancer cells to gemcitabine.","is_dataset_classified":null,"base_score":4.6913478822291435,"endowment":4.6913478822291435,"datacite_reuse_total":2,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19519883","pmcid":"PMC2702280","openalex_id":"https://openalex.org/W2125026963","authors":[],"funders":[{"funder_name":"NCI NIH HHS","grant_id":"P01 CA109552","title":null},{"funder_name":"National Institutes of Health","grant_id":"5P01CA109552-02","title":"Targets to Therapeutics in Pancreatic Cancer"}],"total_grants":2,"fwci":6.5467,"citation_percentile":0.97654739,"influential_citations":0,"citation_trend":[{"year":2012,"count":20},{"year":2013,"count":9},{"year":2014,"count":9},{"year":2015,"count":10},{"year":2016,"count":4},{"year":2017,"count":3},{"year":2018,"count":3},{"year":2019,"count":6},{"year":2020,"count":1},{"year":2021,"count":5},{"year":2023,"count":4},{"year":2024,"count":1},{"year":2025,"count":1}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://link.springer.com/content/pdf/10.1186/1479-5876-7-43.pdf","host_type":"journal"},{"url":"https://link.springer.com/content/pdf/10.1186/1479-5876-7-43.pdf","host_type":"GOLD"},{"url":"https://link.springer.com/content/pdf/10.1186/1479-5876-7-43.pdf","host_type":"publisher"},{"url":"http://link.springer.com/content/pdf/10.1186/1479-5876-7-43.pdf","host_type":"publisher"},{"url":"http://link.springer.com/article/10.1186/1479-5876-7-43/fulltext.html","host_type":"publisher"},{"url":"https://doi.org/10.1186/1479-5876-7-43","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/19519883","host_type":"repository"},{"url":"https://doaj.org/article/e87a44bc51f84ad78a2956d38d23463f","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/2702280","host_type":"repository"},{"url":"http://www.biomedcentral.com/content/pdf/1479-5876-7-43.pdf","host_type":"BioMedCentral"},{"url":"http://www.biomedcentral.com/1479-5876/7/43/abstract","host_type":"BioMedCentral"},{"url":"http://www.biomedcentral.com/1479-5876/7/43","host_type":"BioMedCentral"},{"url":"https://europepmc.org/articles/PMC2702280","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC2702280?pdf=render","host_type":"Europe_PMC"},{"url":"https://translational-medicine.biomedcentral.com/track/pdf/10.1186/1479-5876-7-43","host_type":""},{"url":"http://dx.doi.org/10.1186/1479-5876-7-43","host_type":""},{"url":"https://dx.doi.org/10.1186/1479-5876-7-43","host_type":""}],"fields_of_study":["RNA Interference and Gene Delivery","MicroRNA in disease regulation","Prostate Cancer Treatment and Research","Medicine","Biology","0301 basic medicine","03 medical and health sciences","Aged","Alkaloids","Antimetabolites, Antineoplastic","Carbazoles","Cell Line, Tumor","Cell Survival","Checkpoint Kinase 1","Deoxycytidine","Dose-Response Relationship, Drug","Electric Impedance","Enzyme Inhibitors","Female","Gene Silencing","Humans","Male","Middle Aged","Pancreatic Neoplasms","Protein Kinases","RNA Interference","RNA, Small Interfering","Reproducibility of Results","Transfection","Gemcitabine"],"mesh_terms":["Checkpoint Kinase 1","Gemcitabine","Aged","Alkaloids","Antimetabolites, Antineoplastic","Carbazoles","Cell Survival","Deoxycytidine","Dose-Response Relationship, Drug","Enzyme Inhibitors","Female","Humans","Male","Middle Aged","Pancreatic Neoplasms","Protein Kinases","Transfection","Reproducibility of Results","Electric Impedance","Gene Silencing","RNA Interference","RNA, Small Interfering","Cell Line, Tumor"],"keywords":["Gemcitabine","Pancreatic cancer","Cancer research","CHEK1","Cancer","RNA interference","Kinase","Pharmacology","Synthetic lethality","Medicine","Cancer cell","Biology","Internal medicine","Oncology","Cell cycle","Cell cycle checkpoint","Gene","Cell biology","Biochemistry","Male","Antimetabolites, Antineoplastic","Cell Survival","Carbazoles","Deoxycytidine","Alkaloids","Cell Line, Tumor","Electric Impedance","Humans","Gene Silencing","Enzyme Inhibitors","RNA, Small Interfering","Aged","Medicine(all)","Dose-Response Relationship, Drug","Biochemistry, Genetics and Molecular Biology(all)","Research","R","Middle Aged","Pancreatic Neoplasms","Checkpoint Kinase 1","Female","Protein Kinases"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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