{"doi":"10.1101/gad.351037.123","title":"Stromal-derived NRG1 enables oncogenic KRAS bypass in pancreas cancer","abstract":"Activating KRAS mutations (KRAS*) in pancreatic ductal adenocarcinoma (PDAC) drive anabolic metabolism and support tumor maintenance. KRAS* inhibitors show initial antitumor activity followed by recurrence due to cancer cell-intrinsic and immune-mediated paracrine mechanisms. Here, we explored the potential role of cancer-associated fibroblasts (CAFs) in enabling KRAS* bypass and identified CAF-derived NRG1 activation of cancer cell ERBB2 and ERBB3 receptor tyrosine kinases as a mechanism by which KRAS*-independent growth is supported. Genetic extinction or pharmacological inhibition of KRAS* resulted in up-regulation of ERBB2 and ERBB3 expression in human and murine models, which prompted cancer cell utilization of CAF-derived NRG1 as a survival factor. Genetic depletion or pharmacological inhibition of ERBB2/3 or NRG1 abolished KRAS* bypass and synergized with KRAS G12D inhibitors in combination treatments in mouse and human PDAC models. Thus, we found that CAFs can contribute to KRAS* inhibitor therapy resistance via paracrine mechanisms, providing an actionable therapeutic strategy to improve the effectiveness of KRAS* inhibitors in PDAC patients.","journal":"Genes & Development","year":2023,"id":389613,"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":25,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9475,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1160136,"name":"Jiaqian Xu","orcid":"0000-0002-5218-2710","position":1,"is_corresponding":false},{"id":272523,"name":"Yonghong Liu","orcid":"0000-0001-8327-3108","position":2,"is_corresponding":false},{"id":553762,"name":"Shaoheng Liang","orcid":"0000-0002-9575-1522","position":3,"is_corresponding":false},{"id":299138,"name":"Kyle A. LaBella","orcid":"0000-0002-0473-9262","position":4,"is_corresponding":false},{"id":299134,"name":"Deepavali Chakravarti","orcid":"0000-0002-3961-4734","position":5,"is_corresponding":false},{"id":243058,"name":"Denise J. Spring","orcid":"0000-0002-4593-0901","position":6,"is_corresponding":false},{"id":1018813,"name":"Yan Xia","orcid":"0000-0001-6935-6038","position":7,"is_corresponding":false},{"id":7904,"name":"Ronald A. DePinho","orcid":"0000-0002-5625-577X","position":8,"is_corresponding":false},{"id":573949,"name":"Jincheng Han","orcid":"0000-0002-7751-6158","position":0,"is_corresponding":true}],"reference_count":31,"raw_metadata":null,"created_at":"2026-07-19T01:18:27.054415Z","pmid":"37775182","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":[]}