A RAS(ON) multi-selective inhibitor combination therapy triggers long-term tumor control through senescence-associated tumor-immune equilibrium in pancreatic ductal adenocarcinoma Journal Article
| Authors: | Broderick, C.; Mezzadra, R.; Sisso, E. M.; Mbuga, F.; Raghulan, R.; Chaves-PeĢrez, A.; Kulick, A.; Jiang, L.; Jiang, J.; Ho, Y. J.; Simon, J.; Rosiek, E.; Chan, E.; Filliol, A.; Chaligne, R.; de Stanchina, E.; Pechuan-Jorge, X.; Schietinger, A.; Singh, M.; Lowe, S. W. |
| Article 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. This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine |
| Keywords: | genetics; pyridines; pancreatic neoplasms; antineoplastic agent; mouse; animal; animals; mice; antineoplastic combined chemotherapy protocols; carcinoma, pancreatic ductal; drug effect; drug screening; pathology; xenograft model antitumor assays; cell line, tumor; disease model; immunology; pancreas tumor; tumor cell line; piperazines; drug therapy; disease models, animal; piperazine derivative; cell aging; pyridine derivative; tumor microenvironment; pancreatic ductal carcinoma; cellular senescence; humans; human; palbociclib |
| Journal Title: | Cancer Discovery |
| Volume: | 15 |
| Issue: | 8 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2025-08-01 |
| Start Page: | 1717 |
| End Page: | 1739 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-24-1425 |
| PUBMED: | 40299790 |
| PROVIDER: | scopus |
| PMCID: | PMC12319406 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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