Treatment resistance to platinum-based chemotherapy in lung and ovarian cancer is driven by a targetable TGFβ senescent secretome
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 Rodríguez Mulero, Mercedes Jimenez-Linan, Ljiljana Fruk, Carla P. Martins, Mariano Barbacid, Vassilis G Gorgoulis, James E. Korkola, Doris M. Rassl, Gary J. Doherty, Robert C. Rintoul, Masashi Narita, James D. Brenton, Daniel Muñoz-Espín
Abstract
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 Kras G12V -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.