Journal Article

DKFZ-2026-01792

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Oncogene inactivation-induced senescence facilitates tumor relapse.

Schmitt, P. ; Hönig, K. ; Norcia, M. T.DKFZ* ; Nogueira, M. F. ; Flore, V. ; Vesperinas, I. S. ; Villoro-Agud, M.DKFZ* ; Peng, L.DKFZ* ; Safyürek, Z.DKFZ* ; Tariq, M.DKFZ* ; Milojkovic, A. ; Anders, K. ; Schröck, E.DKFZ* ; Sauer, S. ; Uyar, B. ; Akalin, A. ; Willimsky, G.DKFZ* ; Haas, S.DKFZ* ; Martínez-Reyes, I.DKFZ* ; Blankenstein, T.

2026
Springer Nature [London]

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 BRAFV600E 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.

Keyword(s): Animals (MeSH) ; Humans (MeSH) ; Proto-Oncogene Proteins B-raf: genetics (MeSH) ; Proto-Oncogene Proteins B-raf: metabolism (MeSH) ; Tumor Microenvironment: genetics (MeSH) ; Oncogenes: genetics (MeSH) ; Cellular Senescence: genetics (MeSH) ; Cell Line, Tumor (MeSH) ; Mice (MeSH) ; Vemurafenib: pharmacology (MeSH) ; Senescence-Associated Secretory Phenotype: genetics (MeSH) ; Neoplasm Recurrence, Local: genetics (MeSH) ; Neoplasm Recurrence, Local: pathology (MeSH) ; Proto-Oncogene Proteins c-mdm2: metabolism (MeSH) ; Proto-Oncogene Proteins c-mdm2: genetics (MeSH) ; Melanoma: genetics (MeSH) ; Melanoma: pathology (MeSH) ; Melanoma: drug therapy (MeSH) ; Chromosomal Instability (MeSH) ; Polyploidy (MeSH) ; Proto-Oncogene Proteins B-raf ; Vemurafenib ; BRAF protein, human ; Proto-Oncogene Proteins c-mdm2

Note: #DKTKZFB26# / #NCTZFB26#

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Berlin (BE01)
2. DKTK Koordinierungsstelle Dresden (DD01)
3. Koordinierungsstelle NCT Dresden (DD04)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2026

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