{"doi":"10.1158/2159-8290.cd-24-0489","title":"Combined KRAS Inhibition and Immune Therapy Generates Durable Complete Responses in an Autochthonous PDAC Model","abstract":"Abstract Pancreatic ductal adenocarcinoma (PDAC) resists conventional chemo/radiation and immunotherapy (IO). In PDAC, oncogenic KRAS (KRAS*) drives glycolysis in cancer cells to consume available glucose and produce abundant lactate, creating profound immune suppression in the tumor microenvironment. In this study, we combined KRAS* inhibition with agents targeting the major arms of the immunity cycle: CXCR1/2 inhibitor for myeloid cells, antagonistic anti-LAG3 antibody for T cells, and agonistic anti-41BB antibody for dendritic cells. This combination elicited robust antitumor regression in iKPC mice bearing large autochthonous tumors. Whereas untreated mice succumbed within 3 weeks, sustained treatment led to durable complete tumor regression and prolonged survival in 36% of mice at 6 months. Mechanistic analyses revealed enhanced T-cell infiltration and activation, depletion of immunosuppressive myeloid cells, and increased antigen cross-presentation by dendritic cells within the tumor core. These findings highlight the promise of KRAS* inhibitors alongside IO as a potential PDAC treatment avenue, warranting clinical investigation. Significance: Clinically available KRAS* inhibitors and IO agents alleviated the immunosuppressive tumor microenvironment in PDAC. Profound tumor regression and prolonged survival in an autochthonous PDAC model provide a compelling rationale for combining KRAS* inhibition with IO agents targeting multiple arms of the immunity cycle to combat PDAC.","journal":"Cancer Discovery","year":2024,"id":421708,"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":29,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9528,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":573949,"name":"Jincheng Han","orcid":"0000-0002-7751-6158","position":1,"is_corresponding":false},{"id":243054,"name":"Wen‐Hao Hsu","orcid":"0000-0001-9050-8227","position":2,"is_corresponding":false},{"id":299138,"name":"Kyle A. LaBella","orcid":"0000-0002-0473-9262","position":3,"is_corresponding":false},{"id":274891,"name":"Pingna Deng","orcid":"0000-0001-9716-4113","position":4,"is_corresponding":false},{"id":274885,"name":"Xiaoying Shang","orcid":"0009-0004-2398-4855","position":5,"is_corresponding":false},{"id":990373,"name":"Paulino Tallón de Lara","orcid":"0000-0001-7368-4798","position":6,"is_corresponding":false},{"id":274881,"name":"Li Cai","orcid":"0000-0002-2160-5055","position":7,"is_corresponding":false},{"id":1018812,"name":"Shan Jiang","orcid":"0000-0002-2042-5298","position":8,"is_corresponding":false},{"id":7904,"name":"Ronald A. DePinho","orcid":"0000-0002-5625-577X","position":9,"is_corresponding":false},{"id":1214645,"name":"Yonghong Liu","orcid":"0000-0003-2609-7720","position":0,"is_corresponding":true}],"reference_count":67,"raw_metadata":null,"created_at":"2026-07-19T01:57:41.370244Z","pmid":"39348506","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":[]}