{"doi":"10.1101/2023.08.29.552598","title":"<i>Kras</i>\n                  loss of heterozygosity promotes MAPK dependent pancreatic ductal adenocarcinoma and induces therapeutic sensitivity","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  Pancreatic cancer is characterised by the prevalence of oncogenic mutations in\n                  <jats:italic>KRAS</jats:italic>\n                  . Previous studies have reported that altered\n                  <jats:italic>Kras</jats:italic>\n                  gene dosage drives progression and metastatic incidence in pancreatic cancer. While the role of oncogenic\n                  <jats:italic>KRAS</jats:italic>\n                  mutation is well characterised, the relevance of the partnering wild-type\n                  <jats:italic>KRAS</jats:italic>\n                  allele in pancreatic cancer is less well understood and controversial. Using\n                  <jats:italic>in vivo</jats:italic>\n                  mouse modelling of pancreatic cancer, we demonstrate that wild-type\n                  <jats:italic>Kras</jats:italic>\n                  restrains the oncogenic impact of mutant\n                  <jats:italic>Kras</jats:italic>\n                  , and drastically impacts both\n                  <jats:italic>Kras</jats:italic>\n                  -mediated tumourigenesis and therapeutic response. Mechanistically, deletion of wild-type\n                  <jats:italic>Kras</jats:italic>\n                  increases oncogenic\n                  <jats:italic>Kras</jats:italic>\n                  signalling through the downstream MAPK effector pathway, driving pancreatic intraepithelial neoplasia (PanIN) initiation. In addition, in the KPC mouse model, a more aggressive model of pancreatic cancer, loss of wild-type KRAS leads to accelerated initiation but delayed tumour progression. These tumours had altered stroma, downregulated\n                  <jats:italic>Myc</jats:italic>\n                  levels and an enrichment for immunogenic gene signatures. Importantly, loss of wild-type\n                  <jats:italic>Kras</jats:italic>\n                  sensitises\n                  <jats:italic>Kras</jats:italic>\n                  mutant tumours to MEK1/2 inhibition though tumours eventually become resistant and then rapidly progress. This study demonstrates the repressive role of wild-type\n                  <jats:italic>Kras</jats:italic>\n                  during pancreatic tumourigenesis and highlights the critical impact of the presence of wild-type KRAS on tumourigenesis and therapeutic response in pancreatic cancer.\n                </jats:p>","journal":null,"year":null,"id":614423,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"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":1487786,"name":"Arafath K. Najumudeen","orcid":"0000-0002-3764-5721","position":1,"is_corresponding":false},{"id":666710,"name":"Catriona A. Ford","orcid":"0000-0003-3991-6369","position":2,"is_corresponding":false},{"id":65374,"name":"Kathryn Gilroy","orcid":"0000-0003-4607-194X","position":3,"is_corresponding":false},{"id":252083,"name":"Rosanna Upstill‐Goddard","orcid":"0000-0002-2666-0934","position":4,"is_corresponding":false},{"id":13335,"name":"David K. Chang","orcid":"0000-0002-4821-3078","position":5,"is_corresponding":false},{"id":549954,"name":"William Clark","orcid":"0009-0004-8982-8564","position":6,"is_corresponding":false},{"id":65386,"name":"Colin Nixon","orcid":"0000-0002-8085-2160","position":7,"is_corresponding":false},{"id":250681,"name":"Simon T. Barry","orcid":"0000-0002-8511-0588","position":8,"is_corresponding":false},{"id":699447,"name":"Jennifer P. Morton","orcid":"0000-0001-5766-9141","position":9,"is_corresponding":false},{"id":65390,"name":"Andrew D. Campbell","orcid":"0000-0003-3930-1276","position":10,"is_corresponding":false},{"id":65393,"name":"Owen J. Sansom","orcid":"0000-0001-9540-3010","position":11,"is_corresponding":false},{"id":1524581,"name":"Sigrid K. Fey","orcid":"0009-0007-3667-513X","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"<i>Kras</i>\n                  loss of heterozygosity promotes MAPK dependent pancreatic ductal adenocarcinoma and induces therapeutic sensitivity","abstract":"<jats:title>Abstract</jats:title>\n                <jats:p>\n                  Pancreatic cancer is characterised by the prevalence of oncogenic mutations in\n                  <jats:italic>KRAS</jats:italic>\n                  . Previous studies have reported that altered\n                  <jats:italic>Kras</jats:italic>\n                  gene dosage drives progression and metastatic incidence in pancreatic cancer. While the role of oncogenic\n                  <jats:italic>KRAS</jats:italic>\n                  mutation is well characterised, the relevance of the partnering wild-type\n                  <jats:italic>KRAS</jats:italic>\n                  allele in pancreatic cancer is less well understood and controversial. Using\n                  <jats:italic>in vivo</jats:italic>\n                  mouse modelling of pancreatic cancer, we demonstrate that wild-type\n                  <jats:italic>Kras</jats:italic>\n                  restrains the oncogenic impact of mutant\n                  <jats:italic>Kras</jats:italic>\n                  , and drastically impacts both\n                  <jats:italic>Kras</jats:italic>\n                  -mediated tumourigenesis and therapeutic response. Mechanistically, deletion of wild-type\n                  <jats:italic>Kras</jats:italic>\n                  increases oncogenic\n                  <jats:italic>Kras</jats:italic>\n                  signalling through the downstream MAPK effector pathway, driving pancreatic intraepithelial neoplasia (PanIN) initiation. In addition, in the KPC mouse model, a more aggressive model of pancreatic cancer, loss of wild-type KRAS leads to accelerated initiation but delayed tumour progression. These tumours had altered stroma, downregulated\n                  <jats:italic>Myc</jats:italic>\n                  levels and an enrichment for immunogenic gene signatures. Importantly, loss of wild-type\n                  <jats:italic>Kras</jats:italic>\n                  sensitises\n                  <jats:italic>Kras</jats:italic>\n                  mutant tumours to MEK1/2 inhibition though tumours eventually become resistant and then rapidly progress. This study demonstrates the repressive role of wild-type\n                  <jats:italic>Kras</jats:italic>\n                  during pancreatic tumourigenesis and highlights the critical impact of the presence of wild-type KRAS on tumourigenesis and therapeutic response in pancreatic cancer.\n                </jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"23304386","pmcid":null,"openalex_id":"https://openalex.org/W4386293350","authors":[],"funders":[],"total_grants":0,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"green","license":null,"oa_locations":[{"url":"https://www.biorxiv.org/content/biorxiv/early/2023/08/29/2023.08.29.552598.full.pdf","host_type":"repository"},{"url":"https://www.biorxiv.org/content/biorxiv/early/2023/08/29/2023.08.29.552598.full.pdf","host_type":"repository"},{"url":"https://syndication.highwire.org/content/doi/10.1101/2023.08.29.552598","host_type":"publisher"},{"url":"http://dx.doi.org/10.1101/2023.08.29.552598","host_type":"repository"}],"fields_of_study":["Pancreatic and Hepatic Oncology Research","Cancer Genomics and Diagnostics","Cancer Cells and Metastasis"],"mesh_terms":[],"keywords":["KRAS","Pancreatic Intraepithelial Neoplasia","Pancreatic cancer","Cancer research","Biology","Wild type","Cancer","Adenocarcinoma","Mutant","Medicine","Internal medicine","Colorectal cancer","Gene","Genetics"],"sdg_mappings":[{"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":"2026-08-02T13:18:22.434550Z","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":[]}