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| Item Type: | Article |
|---|---|
| Title: | Oncogene inactivation-induced senescence facilitates tumor relapse |
| Creators: |
Schmitt, Philipp  ORCID: https://orcid.org/0009-0008-1643-0079, Hönig, Katrin, Norcia, Maria Teresa ORCID: https://orcid.org/0009-0007-8042-4530, Nogueira, Marta F. ORCID: https://orcid.org/0000-0002-7607-4570, Flore, Viktoria ORCID: https://orcid.org/0009-0001-3023-433X, Vesperinas, Inés Simó ORCID: https://orcid.org/0000-0001-8965-127X, Villoro-Agud, Maria ORCID: https://orcid.org/0009-0005-5525-0589, Peng, Lushan, Safyürek, Zuhal ORCID: https://orcid.org/0009-0004-8412-5069, Tariq, Mehreen ORCID: https://orcid.org/0009-0003-5217-2226, Milojkovic, Ana ORCID: https://orcid.org/0009-0001-7621-2283, Anders, Kathleen ORCID: https://orcid.org/0000-0002-0429-200X, Schröck, Evelin ORCID: https://orcid.org/0000-0002-3377-1704, Sauer, Sascha ORCID: https://orcid.org/0000-0002-4794-3693, Uyar, Bora ORCID: https://orcid.org/0000-0002-3170-4890, Akalin, Altuna ORCID: https://orcid.org/0000-0002-0468-0117, Willimsky, Gerald ORCID: https://orcid.org/0000-0002-9693-948X, Haas, Simon ORCID: https://orcid.org/0000-0001-9227-2051, Martínez-Reyes, Inmaculada ORCID: https://orcid.org/0000-0003-0479-1535 and Blankenstein, Thomas ORCID: https://orcid.org/0000-0002-3357-4321
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| Abstract: | Oncogene-directed therapies can induce profound tumor regression in oncogene-addicted cancers, but their long-term benefit is often limited by resistance and relapse. Here we show that oncogene inactivation rapidly induces senescence and a pro-inflammatory senescence-associated secretory phenotype (SASP). In vivo, oncogene inactivation-induced senescence (OIIS) predisposes tumors to relapse, accompanied by polyploidy, chromosomal instability, acquisition of alternative oncogenic pathways including mouse double minute 2 homolog (Mdm2) upregulation, and tumor microenvironmental remodeling toward neovascularization and immunosuppression. Spectral flow cytometry reveals a shift from an immune-activated to an immunosuppressive milieu during relapse. OIIS features are also observed in human BRAF(V600E) melanoma cells treated with vemurafenib, supporting clinical relevance. Together, our findings establish OIIS as a double-edged process: it initially restrains tumor growth but simultaneously creates conditions that favor recurrence. By defining the genetic, metabolic and microenvironmental hallmarks of OIIS, our study highlights adaptations to oncogene deprivation that limit the durability of targeted therapies. |
| Keywords: | Animals, Mice |
| Source: | Nature Communications |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 17 |
| Page Range: | 6244 |
| Date: | 15 July 2026 |
| Official Publication: | https://doi.org/10.1038/s41467-026-75021-9 |
| PubMed: | View item in PubMed |
| Related to: |
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