ArticleTranslational oncology2025
KRAS inhibition reverses chemotherapy resistance promoted by therapy-induced senescence-like in pancreatic ductal adenocarcinoma.
Article in Translational oncology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Review
- Impact of Tumor Genomic Profile on Adjuvant Chemotherapy Efficacy in Resected Pancreatic Adenocarcinoma: Results From the PRODIGE-24/CCTG PA6 Study.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2026Article
- Chemotherapy-induced senescence promotes stroma stiffness and antioxidant adaptation to promote chemoresistance in pancreatic ductal adenocarcinoma.Nature communications · 2026Article
- Precision Medicine in Pancreatic Cancer: Targeting KRAS and Beyond.Targeted oncology · 2026Review
- Lactylation-driven KRT19 promotes non-small cell lung cancer progression by suppressing cellular senescence.Journal of experimental & clinical cancer research : CR · 2025Article
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Authors and funding
10 authors.
Funding
Abstract
backgroundEmerging evidence suggests that chemotherapy can accumulate senescent-like cells within tumor tissues, a phenomenon linked to therapy resistance. The aim of this study is to analyze the senescence-like state of after-treatment persistent cells associated with KRAS mutational status to offer a therapeutic strategy to target these cells in pancreatic ductal adenocarcinoma (PDAC). EXPERIMENTAL
designThree commercial cell lines and five patient-derived primary cell cultures with different KRAS statuses were studied following gemcitabine treatment. Senescence-like status was assessed using SA-β-gal, together with cell cycle regulators such as p21. Additionally, KRAS mutations were modulated using MRTX1133 and AMG-510, and the signaling pathways ERK and AKT were analyzed and modulated in vitro. Finally, p21 expression, associated with the senescence-like state, on patient outcomes and treatment response was analyzed in publicly available bulk RNA-seq and single-nucleus datasets.
resultsWe observed an overexpression of p21 alongside an increase in SA-β-gal signal in response to gemcitabine treatment, indicating the induction of a senescence-like state. Specific inhibition of KRAS G12D or G12C mutations reduced SA-β-gal signal and sensitized PDAC cells to gemcitabine. Moreover, ERK inhibition but not AKT inhibition decreased SA-β-gal signal. Additionally, we characterized p21 expression levels in relation to patient outcomes and found that they are modulated by treatment.
conclusionsThis dual-targeted therapeutic strategy holds promises for overcoming the challenges posed by KRAS-driven cancers, particularly in addressing the formidable obstacle of pancreatic cancer.
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