{"doi":"10.1158/2159-8290.cd-24-1425","title":"A RAS(ON) Multi-Selective Inhibitor Combination Therapy Triggers Long-term Tumor Control through Senescence-Associated Tumor-Immune Equilibrium in Pancreatic Ductal Adenocarcinoma","abstract":"Pharmacological inhibition of oncogenic RAS represents an attractive strategy to target pancreatic ductal adenocarcinoma (PDAC), an almost ubiquitously RAS-driven disease. However, initial responses to targeted monotherapy inhibition of active RAS can be followed by relapses, potentially driven by the persistence of drug-tolerant tumor cells. To target these \"persister\" cells, we investigated strategies to increase their immune visibility in mouse models of PDAC. We show that combining a RAS(ON) multi-selective inhibitor with the CDK4/6 inhibitor palbociclib drives persister cells into a senescent-like state, which coincides with improved tumor control and substantial remodeling of the tumor microenvironment. Combining RAS(ON) and CDK4/6 inhibition with a CD40 agonist results in durable regressions and CD4 T cell-dependent tumor-immune equilibrium. Our studies reveal a combinatorial approach that circumvents resistance to RAS(ON) inhibitor monotherapy in preclinical models and demonstrates a mechanism by which therapy-induced senescence can be reinforced by the immune system, resulting in durable tumor control. SIGNIFICANCE: Our preclinical studies highlight an opportunity to exploit the senescence program and CD4 T cell-mediated mechanisms to achieve long-term tumor-immune equilibrium and control with RAS-targeted therapies. This work advances our understanding of therapy-induced senescence and suggests new avenues for combination therapies with the potential to benefit patients with PDAC. See related commentary by Lasse Opsahl and Pasca di Magliano, p. 1537.","journal":"Cancer Discovery","year":2025,"id":511531,"datarank":0.42498200160843247,"base_score":2.833213344056216,"endowment":2.833213344056216,"self_citation_contribution":0.42498200160843247,"citation_network_contribution":0.0,"self_endowment_contribution":0.42498200160843247,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9494,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":228774,"name":"Riccardo Mezzadra","orcid":"0000-0002-7737-8461","position":1,"is_corresponding":false},{"id":664183,"name":"Exequiel M. Sisso","orcid":null,"position":2,"is_corresponding":false},{"id":1369545,"name":"Felix Mbuga","orcid":"0009-0002-0542-9669","position":3,"is_corresponding":false},{"id":1204688,"name":"Rashi Raghulan","orcid":null,"position":4,"is_corresponding":false},{"id":845993,"name":"Almudena Chaves Perez","orcid":"0000-0002-2663-4672","position":5,"is_corresponding":false},{"id":218301,"name":"Amanda Kulick","orcid":"0000-0001-7365-4142","position":6,"is_corresponding":false},{"id":1369546,"name":"Lingyan Jiang","orcid":"0009-0006-7523-6968","position":7,"is_corresponding":false},{"id":1203803,"name":"Jingjing Jiang","orcid":"0009-0004-2766-025X","position":8,"is_corresponding":false},{"id":218294,"name":"Yu-Jui Ho","orcid":"0000-0002-7540-024X","position":9,"is_corresponding":false},{"id":229913,"name":"Janelle Simon","orcid":null,"position":10,"is_corresponding":false},{"id":998155,"name":"Eric Rosiek","orcid":"0000-0001-6355-1457","position":11,"is_corresponding":false},{"id":1034408,"name":"Eric Chan","orcid":"0009-0002-2835-3994","position":12,"is_corresponding":false},{"id":615134,"name":"Aveline Filliol","orcid":"0000-0002-1345-8147","position":13,"is_corresponding":false},{"id":80327,"name":"Ronan Chaligné","orcid":"0000-0003-4332-3291","position":14,"is_corresponding":false},{"id":225995,"name":"Elisa de Stanchina","orcid":"0000-0002-3873-315X","position":15,"is_corresponding":false},{"id":874250,"name":"Ximo Pechuan-Jorge","orcid":"0000-0001-8938-7931","position":16,"is_corresponding":false},{"id":477282,"name":"Andrea Schietinger","orcid":"0000-0003-3644-1687","position":17,"is_corresponding":false},{"id":333844,"name":"Mallika Singh","orcid":"0009-0003-0234-1589","position":18,"is_corresponding":false},{"id":218307,"name":"Scott W. Lowe","orcid":"0000-0002-5284-9650","position":19,"is_corresponding":false},{"id":842067,"name":"Caroline Broderick","orcid":"0000-0001-5733-8625","position":0,"is_corresponding":true}],"reference_count":102,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:47:55.918021Z","pmid":"40299790","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":[]}