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

TY - JOUR

T1 - Treatment resistance to platinum-based chemotherapy in lung and ovarian cancer is driven by a targetable TGFβ senescent secretome

AU - González-Gualda, Estela

AU - Reinius, Marika A.V.

AU - Macias, David

AU - Morsli, Samir

AU - Ge, Jianfeng

AU - Olan, Ioana

AU - Martín, José Ezequiel

AU - Ou, Hui Ling

AU - Hartono, Muhamad

AU - Puerto-Camacho, María Pilar

AU - Denholm, Mary

AU - Kieran, Rosalind

AU - Hoffmann, Reuben

AU - Dane, Mark

AU - Veroutis, Dimitris

AU - Medrano, Guillermo

AU - Mulero, Francisca

AU - Jimenez-Linan, Mercedes

AU - Fruk, Ljiljana

AU - Martins, Carla P.

AU - Barbacid, Mariano

AU - Gorgoulis, Vassilis

AU - Korkola, James E.

AU - Rassl, Doris M.

AU - Doherty, Gary J.

AU - Rintoul, Robert C.

AU - Narita, Masashi

AU - Brenton, James D.

AU - Muñoz-Espín, Daniel

N1 - Publisher Copyright: © The Author(s) 2026.

PY - 2026/2

Y1 - 2026/2

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105029273616

U2 - 10.1038/s43587-025-01054-2

DO - 10.1038/s43587-025-01054-2

M3 - Article

C2 - 41634464

AN - SCOPUS:105029273616

VL - 6

SP - 368

EP - 392

JO - Nature Aging

JF - Nature Aging

IS - 2

ER -