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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月3日

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  • Estela González-Gualda,
  • Marika A. V. Reinius,
  • David Macias,
  • Samir Morsli,
  • Jianfeng Ge,
  • Ioana Olan,
  • José Ezequiel Martín,
  • Hui-Ling Ou,
  • Muhamad Hartono,
  • María Pilar Puerto-Camacho,
  • Mary Denholm,
  • Rosalind Kieran,
  • Reuben Hoffmann,
  • Mark Dane,
  • Dimitris Veroutis,
  • Guillermo Medrano,
  • Francisca Mulero,
  • Mercedes Jimenez-Linan,
  • Ljiljana Fruk,
  • Carla P. Martins,
  • Mariano Barbacid,
  • Vassilis Gorgoulis,
  • James E. Korkola,
  • Doris M. Rassl,
  • Gary J. Doherty,
  • Robert C. Rintoul,
  • Masashi Narita,
  • James D. Brenton,
  • Daniel Muñoz-Espín

摘要

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.