{"doi":"10.1158/2159-8290.cd-19-0597","title":"Tumor Microenvironment Remodeling Enables Bypass of Oncogenic KRAS Dependency in Pancreatic Cancer","abstract":"Abstract Oncogenic KRAS (KRAS*) is a key tumor maintenance gene in pancreatic ductal adenocarcinoma (PDAC), motivating pharmacologic targeting of KRAS* and its effectors. Here, we explored mechanisms involving the tumor microenvironment (TME) as a potential basis for resistance to targeting KRAS*. Using the inducible KrasG12D;Trp53−/− PDAC mouse model, gain-of-function screens of epigenetic regulators identified HDAC5 as the top hit enabling KRAS* independent tumor growth. HDAC5-driven escaper tumors showed a prominent neutrophil-to-macrophage switch relative to KRAS*-driven tumors. Mechanistically, HDAC5 represses Socs3, a negative regulator of chemokine CCL2, resulting in increased CCL2, which recruits CCR2+ macrophages. Correspondingly, enforced Ccl2 promotes macrophage recruitment into the TME and enables tumor recurrence following KRAS* extinction. These tumor-associated macrophages in turn provide cancer cells with trophic support including TGFβ to enable KRAS* bypass in a SMAD4-dependent manner. Our work uncovers a KRAS* resistance mechanism involving immune cell remodeling of the PDAC TME. Significance: Although KRAS* is required for PDAC tumor maintenance, tumors can recur following KRAS* extinction. The capacity of PDAC cancer cells to alter the TME myeloid cell composition to support KRAS*-independent tumor growth illuminates novel therapeutic targets that may enhance the effectiveness of therapies targeting KRAS* and its pathway components. See related commentary by Carr and Fernandez-Zapico, p. 910. This article is highlighted in the In This Issue feature, p. 890","journal":"Cancer Discovery","year":2020,"id":51505,"datarank":0.7565137675378871,"base_score":5.043425116919247,"endowment":5.043425116919247,"self_citation_contribution":0.7565137675378871,"citation_network_contribution":0.0,"self_endowment_contribution":0.7565137675378871,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":154,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9486,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":260856,"name":"Avnish Kapoor","orcid":null,"position":1,"is_corresponding":false},{"id":257597,"name":"Qiang Zhang","orcid":"0000-0002-2707-0258","position":2,"is_corresponding":false},{"id":257598,"name":"Jiexi Li","orcid":"0000-0003-1508-5732","position":3,"is_corresponding":false},{"id":1884,"name":"Chang‐Jiun Wu","orcid":"0000-0001-8350-6397","position":4,"is_corresponding":false},{"id":257599,"name":"Jun Li","orcid":"0000-0001-7902-8142","position":5,"is_corresponding":false},{"id":244196,"name":"Zhengdao Lan","orcid":null,"position":6,"is_corresponding":false},{"id":12217,"name":"Ming Tang","orcid":"0000-0002-7739-8913","position":7,"is_corresponding":false},{"id":257600,"name":"Xingdi Ma","orcid":"0000-0002-9263-1883","position":8,"is_corresponding":false},{"id":257601,"name":"Jeffrey J. Ackroyd","orcid":"0000-0003-3796-4447","position":9,"is_corresponding":false},{"id":104298,"name":"Raghu Kalluri","orcid":"0000-0002-2190-547X","position":10,"is_corresponding":false},{"id":230400,"name":"Jianhua Zhang","orcid":"0000-0001-5412-9860","position":11,"is_corresponding":false},{"id":257602,"name":"Shan Jiang","orcid":"0000-0002-8297-0099","position":12,"is_corresponding":false},{"id":243058,"name":"Denise J. Spring","orcid":"0000-0002-4593-0901","position":13,"is_corresponding":false},{"id":39929,"name":"Yanru Wang","orcid":"0000-0001-8272-2450","position":14,"is_corresponding":false},{"id":7904,"name":"Ronald A. DePinho","orcid":"0000-0002-5625-577X","position":15,"is_corresponding":false},{"id":257596,"name":"Pingping Hou","orcid":"0000-0002-2429-0861","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T20:41:30.009880Z","pmid":"32341020","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":[]}