{"doi":"10.1101/227264","title":"An Essential Role for\n                  <i>Argonaute 2</i>\n                  in EGFR-KRAS Signaling in Pancreatic Cancer Development","abstract":"<jats:p>\n                  KRAS and EGFR are known essential mediators of pancreatic cancer development. In addition, KRAS and EGFR have both been shown to interact with and perturb the function of Argonaute 2 (AGO2), a key regulator of RNA-mediated gene silencing. Here, we employed a genetically engineered mouse model of pancreatic cancer to define the effects of conditional loss of\n                  <jats:italic>AGO2</jats:italic>\n                  in\n                  <jats:italic>KRAS</jats:italic>\n                  <jats:sup>\n                    <jats:italic>G12D</jats:italic>\n                  </jats:sup>\n                  -driven pancreatic cancer. Genetic ablation of\n                  <jats:italic>AGO2</jats:italic>\n                  does not interfere with development of the normal pancreas or\n                  <jats:italic>KRAS</jats:italic>\n                  <jats:sup>\n                    <jats:italic>G12D</jats:italic>\n                  </jats:sup>\n                  -driven early precursor pancreatic intraepithelial neoplasia (PanIN) lesions. Remarkably, however,\n                  <jats:italic>AGO2</jats:italic>\n                  is required for progression from early to late PanIN lesions, development of pancreatic ductal adenocarcinoma (PDAC), and metastasis.\n                  <jats:italic>AGO2</jats:italic>\n                  ablation permits PanIN initiation driven by the EGFR-RAS axis, but rather than progressing to PDAC, these lesions undergo profound oncogene-induced senescence (OIS). Loss of\n                  <jats:italic>Trp53</jats:italic>\n                  (p53) in this model obviates the requirement of\n                  <jats:italic>AGO2</jats:italic>\n                  for PDAC development. In mouse and human pancreatic tissues, increased expression of AGO2 and elevated co-localization with RAS at the plasma membrane is associated with PDAC progression. Furthermore, phosphorylation of AGO2\n                  <jats:sup>Y393</jats:sup>\n                  by EGFR disrupts the interaction of wild-type RAS with AGO2 at the membrane, but does not affect the interaction of mutant KRAS with AGO2. ARS-1620, a G12C-specific inhibitor, disrupts the KRAS\n                  <jats:sup>G12C</jats:sup>\n                  -AGO2 interaction specifically in pancreatic cancer cells harboring this mutant, demonstrating that the oncogenic KRAS-AGO2 interaction can be pharmacologically targeted. Taken together, our study supports a biphasic model of pancreatic cancer development: an\n                  <jats:italic>AGO2</jats:italic>\n                  -independent early phase of PanIN formation reliant on EGFR-RAS signaling, and an\n                  <jats:italic>AGO2</jats:italic>\n                  -dependent phase wherein the mutant KRAS-AGO2 interaction is critical to prevent OIS in PanINs and allow progression to PDAC.\n                </jats:p>","journal":null,"year":null,"id":678874,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"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":1212850,"name":"Jean Ching-Yi Tien","orcid":null,"position":1,"is_corresponding":false},{"id":356645,"name":"Ronald F. Siebenaler","orcid":"0000-0003-1583-1547","position":2,"is_corresponding":false},{"id":264858,"name":"Seema Chugh","orcid":"0000-0003-1486-0725","position":3,"is_corresponding":false},{"id":357657,"name":"Vijaya L. Dommeti","orcid":null,"position":4,"is_corresponding":false},{"id":357658,"name":"Sylvia Zelenka-Wang","orcid":null,"position":5,"is_corresponding":false},{"id":356647,"name":"Jessica Waninger","orcid":"0000-0002-5172-5779","position":6,"is_corresponding":false},{"id":1773743,"name":"Kristin M. Juckette","orcid":null,"position":7,"is_corresponding":false},{"id":356649,"name":"Alice Xu","orcid":"0000-0001-5685-6455","position":8,"is_corresponding":false},{"id":1619647,"name":"Xiao-Ming Wang","orcid":null,"position":9,"is_corresponding":false},{"id":357659,"name":"Malay Mody","orcid":null,"position":10,"is_corresponding":false},{"id":356648,"name":"Sanjana Eyunni","orcid":"0009-0006-5101-6506","position":11,"is_corresponding":false},{"id":357660,"name":"Andrew Goodrum","orcid":null,"position":12,"is_corresponding":false},{"id":1773744,"name":"Grace Tsaloff","orcid":null,"position":13,"is_corresponding":false},{"id":1212274,"name":"Yuping Zhang","orcid":"0009-0007-1481-8101","position":14,"is_corresponding":false},{"id":262040,"name":"Ingrid J. Apel","orcid":"0000-0001-7364-0111","position":15,"is_corresponding":false},{"id":636042,"name":"Lisha Wang","orcid":"0000-0002-6482-1073","position":16,"is_corresponding":false},{"id":422614,"name":"Javed Siddiqui","orcid":"0009-0004-8251-4829","position":17,"is_corresponding":false},{"id":512358,"name":"Richard D. Smith","orcid":"0000-0002-1908-3083","position":18,"is_corresponding":false},{"id":476847,"name":"Heather A. Carlson","orcid":"0000-0002-7495-1699","position":19,"is_corresponding":false},{"id":254635,"name":"J.J.G. Tesmer","orcid":"0000-0003-1125-3727","position":20,"is_corresponding":false},{"id":262041,"name":"Xuhong Cao","orcid":"0000-0002-2455-3086","position":21,"is_corresponding":false},{"id":88874,"name":"Jiaqi Shi","orcid":"0000-0003-4893-1587","position":22,"is_corresponding":false},{"id":51784,"name":"Chandan Kumar-Sinha","orcid":null,"position":23,"is_corresponding":false},{"id":225419,"name":"Howard C. Crawford","orcid":"0000-0001-9360-3019","position":24,"is_corresponding":false},{"id":51796,"name":"Arul M. Chinnaiyan","orcid":"0000-0001-9282-3415","position":25,"is_corresponding":false},{"id":356643,"name":"Sunita Shankar","orcid":"0000-0001-8743-7480","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"An Essential Role for\n                  <i>Argonaute 2</i>\n                  in EGFR-KRAS Signaling in Pancreatic Cancer Development","abstract":"<jats:p>\n                  KRAS and EGFR are known essential mediators of pancreatic cancer development. In addition, KRAS and EGFR have both been shown to interact with and perturb the function of Argonaute 2 (AGO2), a key regulator of RNA-mediated gene silencing. Here, we employed a genetically engineered mouse model of pancreatic cancer to define the effects of conditional loss of\n                  <jats:italic>AGO2</jats:italic>\n                  in\n                  <jats:italic>KRAS</jats:italic>\n                  <jats:sup>\n                    <jats:italic>G12D</jats:italic>\n                  </jats:sup>\n                  -driven pancreatic cancer. Genetic ablation of\n                  <jats:italic>AGO2</jats:italic>\n                  does not interfere with development of the normal pancreas or\n                  <jats:italic>KRAS</jats:italic>\n                  <jats:sup>\n                    <jats:italic>G12D</jats:italic>\n                  </jats:sup>\n                  -driven early precursor pancreatic intraepithelial neoplasia (PanIN) lesions. Remarkably, however,\n                  <jats:italic>AGO2</jats:italic>\n                  is required for progression from early to late PanIN lesions, development of pancreatic ductal adenocarcinoma (PDAC), and metastasis.\n                  <jats:italic>AGO2</jats:italic>\n                  ablation permits PanIN initiation driven by the EGFR-RAS axis, but rather than progressing to PDAC, these lesions undergo profound oncogene-induced senescence (OIS). Loss of\n                  <jats:italic>Trp53</jats:italic>\n                  (p53) in this model obviates the requirement of\n                  <jats:italic>AGO2</jats:italic>\n                  for PDAC development. In mouse and human pancreatic tissues, increased expression of AGO2 and elevated co-localization with RAS at the plasma membrane is associated with PDAC progression. Furthermore, phosphorylation of AGO2\n                  <jats:sup>Y393</jats:sup>\n                  by EGFR disrupts the interaction of wild-type RAS with AGO2 at the membrane, but does not affect the interaction of mutant KRAS with AGO2. ARS-1620, a G12C-specific inhibitor, disrupts the KRAS\n                  <jats:sup>G12C</jats:sup>\n                  -AGO2 interaction specifically in pancreatic cancer cells harboring this mutant, demonstrating that the oncogenic KRAS-AGO2 interaction can be pharmacologically targeted. Taken together, our study supports a biphasic model of pancreatic cancer development: an\n                  <jats:italic>AGO2</jats:italic>\n                  -independent early phase of PanIN formation reliant on EGFR-RAS signaling, and an\n                  <jats:italic>AGO2</jats:italic>\n                  -dependent phase wherein the mutant KRAS-AGO2 interaction is critical to prevent OIS in PanINs and allow progression to PDAC.\n                </jats:p>","is_dataset_classified":null,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"21097893","pmcid":null,"openalex_id":"https://openalex.org/W2772313412","authors":[],"funders":[{"funder_name":"National Institutes of Health","grant_id":"4U01CA224145-02","title":"Interrupting Cellular Crosstalk in the Immunosuppressive Microenvironment of Pancreas Cancer"},{"funder_name":"National Institutes of Health","grant_id":"5K08CA234222-03","title":"Linking epigenetic regulation and TGF-β signaling in pancreatic cancer"},{"funder_name":"National Institutes of Health","grant_id":"1R35CA231996-01","title":"Exploring Precision Oncology: From Gene Fusions to lncRNAs"}],"total_grants":3,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[{"year":2019,"count":1},{"year":2023,"count":1}],"oa_status":"green","license":"cc-by","oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2019/08/01/227264.full.pdf","host_type":"repository"},{"url":"https://www.biorxiv.org/content/biorxiv/early/2019/08/01/227264.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/227264","host_type":"publisher"},{"url":"https://doi.org/10.1101/227264","host_type":"repository"},{"url":"https://www.nature.com/articles/s41467-020-16309-2.pdf","host_type":""},{"url":"https://dx.doi.org/10.1101/227264","host_type":""},{"url":"http://dx.doi.org/10.1101/227264","host_type":""}],"fields_of_study":["Pancreatic and Hepatic Oncology Research","RNA modifications and cancer","Cancer-related Molecular Pathways","0301 basic medicine","03 medical and health sciences"],"mesh_terms":[],"keywords":["KRAS","Pancreatic cancer","Pancreatic Intraepithelial Neoplasia","Cancer research","Biology","Cancer","Carcinogenesis","Gene silencing","Pancreas","Argonaute","Small interfering RNA","Cell culture","Endocrinology","Transfection","Genetics","Gene","Colorectal cancer"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. Good health"},{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-17T11:40:49.260436Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}