Treatment resistance to platinum-based chemotherapy in lung and ovarian cancer is driven by a targetable TGFβ senescent secretome
Platinum-based chemotherapy is commonly used for non-small cell lung cancer (NSCLC) and high-grade serous ovarian cancer (HGSOC) treatments, yet clinical outcomes remain poor. Cellular senescence and its associated secretory phenotype (SASP) can have multiple tumor-promoting activities, but both are largely unexplored in these cancers. In this study, using xenograft, orthotopic and Kras<sup>G12V</sup>-driven murine NSCLC models, we demonstrate that cisplatin-induced senescence strongly promotes malignant phenotypes and tumor progression, which is stimulated by aging. Mechanistically, we found that a transforming growth factor-beta (TGFβ)-enriched SASP drives pro-proliferative effects through TGFBR1 and AKT/mTOR. TGFBR1 inhibition with galunisertib or senolytic treatment reduces tumor progression driven by cisplatin-induced senescence, and concomitant use of TGFBR1 inhibitors with platinum-based chemotherapy reduces tumor burden and improves survival. Finally, we validate the translational relevance of tumor-promoting TGFβ-enriched SASP using clinical NSCLC and HGSOC samples from patients who received neoadjuvant platinum-based chemotherapy. Together, our findings identify a potential cancer therapy resistance mechanism and provide preclinical proof of concept for future trials.
Authors
- Mary Denholm (ORCID: https://orcid.org/0000-0001-5875-4487)
- Doris M. Rassl (ORCID: https://orcid.org/0000-0002-7742-0113)
- Guillermo Medrano (ORCID: https://orcid.org/0000-0002-3415-5946)
- James E. Korkola (ORCID: https://orcid.org/0000-0002-0030-6216)
- Gary J. Doherty (ORCID: https://orcid.org/0000-0002-8158-8111)
- Rosalind Kieran (ORCID: https://orcid.org/0000-0002-1789-9855)
- Reuben J. Hoffmann (ORCID: https://orcid.org/0000-0001-9554-2977)
- Dimitris Veroutis
- Diego Macías Saint-Gerons
- Samir Morsli (ORCID: https://orcid.org/0000-0002-0371-0732)
- Mariano Barbacid (ORCID: https://orcid.org/0000-0002-1480-2624)
- Mark A. Dane (ORCID: https://orcid.org/0000-0003-3742-9866)
- Carla P. Martins (ORCID: https://orcid.org/0000-0002-8288-1686)
- Robert C. Rintoul (ORCID: https://orcid.org/0000-0003-3875-3780)
- Estela González‐Gualda (ORCID: https://orcid.org/0000-0003-1558-4259)
- Masashi Narita (ORCID: https://orcid.org/0000-0001-7764-577X)
- Francisca Rodríguez Mulero
- Hui-Ling Ou
- Ljiljana Fruk
- María Pilar Puerto-Camacho
- Muhamad Hartono
- José Ezequiel Martín
- Ioana Olan
- Mercedes Jimenez-Linan
- Vassilis G Gorgoulis
- Marika A. V. Reinius
- Jianfeng Ge
- Daniel Muñoz-Espín
Institutions
- Oregon Health & Science University (US)
- University of Dundee (GB)
- National and Kapodistrian University of Athens (GR)
- University of Cambridge (GB)
- Manchester Academic Health Science Centre (GB)
- Cancer Research UK (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- University of Manchester (GB)
- Cancer Research UK Cambridge Center (GB)
- Spanish National Cancer Research Centre (ES)
- Bridge University (SS)
- Papworth Hospital NHS Foundation Trust (GB)
- AstraZeneca (Netherlands) (NL)
- AstraZeneca (Singapore) (SG)
- Cambridge Mechatronics (United Kingdom) (GB)
- Instituto de Biomedicina de Sevilla (ES)
- Hospital Universitario Virgen del Rocío (ES)
Publication Details
- Journal
- Nature Aging
- Published
- 2026-02-03
- DOI
- https://doi.org/10.1038/s43587-025-01054-2
- Citations
- 2
- Primary Topic
- Telomeres, Telomerase, and Senescence
- Type
- article
- Field-Weighted Citation Impact
- 65.68