ArticleCancer discovery2025
A RAS(ON) Multi-Selective Inhibitor Combination Therapy Triggers Long-term Tumor Control through Senescence-Associated Tumor-Immune Equilibrium in Pancreatic Ductal Adenocarcinoma.
Article in Cancer discovery, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- Senescence-directed nanotherapy ameliorates fibrosis and overcomes immune exclusion in cancer.Science (New York, N.Y.) · 2026Article
- Oncogene inactivation-induced senescence facilitates tumor relapse.Nature communications · 2026Article
- The basal cell state maintains pancreatic cancers by controlling an immunosuppressive circuit.bioRxiv : the preprint server for biology · 2026Article
- The evolving landscape of CDK inhibitor use in breast cancer therapy and beyond.Nature reviews. Drug discovery · 2026Review
- RiboScreenBiomedicines · 2026Review
- A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- KRAS-driven immune exclusion in pancreatic ductal adenocarcinoma: mechanisms and therapeutic reversal.The oncologist · 2026Review
- Current advances in immunotherapy for KRAS-Mutant pancreatic cancer.Clinical and experimental medicine · 2026Review
- Article
- Review
- KRAS Inhibitors in Pancreas Cancer: Facts and Hopes about the Immunotherapy We Have All Been Waiting for.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Review
- RAS signaling and remodeling of the immune microenvironment in pancreatic ductal adenocarcinoma: implications of emerging RAS-targeted therapy.Frontiers in cell and developmental biology · 2026Review
- Research progress on the spatiotemporal dynamics of therapy-induced senescence in remodeling the tumor microenvironment.Frontiers in immunology · 2026Review
- Key Considerations for TargetingDrug design, development and therapy · 2026Review
- Simultaneous targeting of KRAS and CDK4 synergistically induces durable growth arrest in pancreatic cancer cells.Cell death & disease · 2025Article
- The Dual Effects of CDK4/6 Inhibitors on Tumor Immunity.Cancers · 2025Review
- A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Broad-Spectrum RAS Inhibition in Pancreatic Ductal Adenocarcinoma: Mechanistic Advances and Therapeutic Promise.Pharmaceuticals (Basel, Switzerland) · 2025Review
- The rapidly growing landscape of RAS inhibitors: from selective allele blockade to broad inhibition strategies.Molecular oncology · 2025Review
- Tumor nutrient stress gives rise to a drug tolerant cell state in pancreatic cancer.bioRxiv : the preprint server for biology · 2025Article
Corrections and comments
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Authors and funding
20 authors.
Funding
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.