Treatment resistance to platinum-based chemotherapy in lung and ovarian cancer is driven by a targetable TGFβ senescent secretome

  • Nat Aging. 2026 Feb;6(2):368-392. doi: 10.1038/s43587-025-01054-2.
Estela González-Gualda  #  1 ,  Marika A V Reinius  #  2  3  4 ,  David Macias  1  5 ,  Samir Morsli  1 ,  Jianfeng Ge  1 ,  Ioana Olan  2 ,  José Ezequiel Martín  6 ,  Hui-Ling Ou  1 ,  Muhamad Hartono  1  7 ,  María Pilar Puerto-Camacho  1 ,  Mary Denholm  1  3  4 ,  Rosalind Kieran  1  3  4 ,  Reuben Hoffmann  8 ,  Mark Dane  8 ,  Dimitris Veroutis  9 ,  Guillermo Medrano  10 ,  Francisca Mulero  10 ,  Mercedes Jimenez-Linan  11 ,  Ljiljana Fruk  7 ,  Carla P Martins  12 ,  Mariano Barbacid  13 ,  Vassilis Gorgoulis  9  14  15 ,  James E Korkola  8 ,  Doris M Rassl  16 ,  Gary J Doherty  4 ,  Robert C Rintoul  2  16  17 ,  Masashi Narita  2  3 ,  James D Brenton  2  3  4 ,  Daniel Muñoz-Espín  18  19  20
Affiliations
  • 1. Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, UK.
  • 2. Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.
  • 3. Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge, UK.
  • 4. Cambridge University Hospitals NHS Foundation Trust, Department of Oncology, Addenbrooke's Hospital, Cambridge, UK.
  • 5. Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio, CSIC, Universidad de Sevilla, Seville, Spain.
  • 6. CMDL, Department of Oncology, University of Cambridge, Cambridge, UK.
  • 7. Department of Chemical Engineering and Biotechnology, Cambridge University, Cambridge, UK.
  • 8. Department of Biomedical Engineering, Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
  • 9. Department of Histology-Embryology, Medical School, National Kapodistrian University of Athens, Athens, Greece.
  • 10. Molecular Imaging Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • 11. Cambridge University Hospitals NHS Foundation Trust, Department of Pathology, Addenbrooke's Hospital, Cambridge, UK.
  • 12. Early Oncology TDE, Oncology R&D, AstraZeneca, Cambridge, UK.
  • 13. Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • 14. Faculty Institute for Cancer Sciences, Manchester Academic Health Sciences Centre, University of Manchester, Manchester, UK.
  • 15. Department of Clinical Molecular Pathology, Medical School, University of Dundee, Dundee, UK.
  • 16. Royal Papworth Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.
  • 17. Cancer Research UK Cambridge Centre Thoracic Cancer Programme, Cambridge, UK.
  • 18. Early Cancer Institute, Department of Oncology, University of Cambridge, Cambridge, UK. [email protected].
  • 19. Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge, UK. [email protected].
  • 20. Cancer Research UK Cambridge Centre Thoracic Cancer Programme, Cambridge, UK. [email protected].
  • # Contributed equally.
PMID: 41634464 DOI: 10.1038/s43587-025-01054-2
Abstract

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 KrasG12V-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.

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