Treatment resistance to platinum-based chemotherapy in lung and ovarian cancer is driven by a targetable TGFβ senescent secretome.
- 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.
- Authors:
- E González-Gualda, MAV Reinius, D Macias, S Morsli, J Ge, I Olan, JE Martín, H-L Ou, M Hartono, MP Puerto-Camacho, M Denholm, R Kieran, R Hoffmann, M Dane, D Veroutis, G Medrano, F Mulero, M Jimenez-Linan, L Fruk, CP Martins, M Barbacid, V Gorgoulis, JE Korkola, DM Rassl, GJ Doherty, RC Rintoul, M Narita, JD Brenton, D Muñoz-Espín
- Journal:
- Nat Aging
- Publication date:
- 3rd Feb 2026
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- DOI