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

Sep 22, 2026

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Platinum-based chemotherapy is widely used for non-small cell lung cancer and high-grade serous ovarian cancer, yet patient outcomes remain poor due to resistance mechanisms that are not fully resolved. Cellular senescence and the associated secretory phenotype (SASP) can promote tumors, but their roles in these cancers are largely unexplored. Using multiple mouse models and clinical samples, the study shows cisplatin-induced senescence strongly accelerates malignant progression. Mechanistically, a TGFβ-enriched SASP signals through TGFBR1 and AKT/mTOR, and TGFBR1 inhibition with galunisertib reduces tumor burden and improves survival in preclinical settings.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages47

Reading Time1 h 58 min

AccessFree to download

Background

Clinical need and therapy resistance

Senescence and SASP rationale

Results

Cisplatin-induced senescence drives malignant traits

TGFβ-enriched SASP activates TGFBR1–AKT/mTOR

Therapeutic implications

Galunisertib as TGFBR1 inhibition strategy

Translational validation in patient samples

nature aging Article [https://doi.org/10.1038/s43587-025-01054-2](https://doi.org/10.1038/s43587-025-01054-2) Treatment resistance to platinum-based chemotherapy in lung and ovarian cancer is driven by atargetableTGFβ senescent secretome Received: 17 January 2025 Accepted: 11 December 2025 | Published online: 3 February 2026 | | --- | | Check for updates | A list of authors and their affiliations appears atthe end of the paper 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 senescenceandits 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 phenotypesand tumor progression, which is stimulated by aging. Mechanistically, we found that a transforming growth factor-beta (TGFβ)-enriched SASP drives pro-proliferative effects throughTGFBR1 and AKT/mTOR. TGFBR1 inhibition with galunisertibor senolytic treatment reduces tumor progression driven by cisplatin-induced senescence, and concomitant use ofTGFBR1 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. Lung cancer accounts for the highest proportion of cancer-related deaths worldwide, with more than 1.8 million deaths annually. Although therapy with immune checkpoint and EGFR inhibitors has substantially improved outcomesin selected patients, platinum-based therapy, either alone or in other combinations, remains an essential standard-of-care treatment for most patients with lung cancer1. Platinum-based therapy also has high efficacy in cancers with high chromosomal instability, particularly HGSOC2–4. Recent studies on cytotoxic resistance have focused on genetic and non-genetic evolutionin the cell-autonomous tumor compartment that can generate complex cellular resistance traits5–7. However, platinum-based therapy may induce adverse tumor microenvironment phenotypes that drive resistance by crosstalk with the cell-autonomous tumor compartment. Platinum-based chemotherapy results in increased levels of intratumoral and stromal senescence-associated β-galactosidase (SA-β-gal) activity in NSCLC, indicating cellular senescence8. Additional studies have demonstrated the accumulation ofsenescent cells in different human tumor types after neoadjuvant chemotherapy (NACT), including breast, mesothelioma, prostate, renal cell and rectal cancers9, suggesting that senescence is a common response to anticancer therapies10. A key hallmark of senescence is strong paracrine secretion of cytokines, growth factors, proteases and other mediators, jointly named the senescence-associated secretory phenotype (SASP)11. Senescenceis considered a tumor-suppressive mechanism, but increasing evidence indicates that persistent senescent cells can also drive potent tumor-promoting effects ina paracrine manner12,13. [e-mail:](e-mail: dm742@cam.ac.uk)[ dm742@cam.ac.uk](e-mail: dm742@cam.ac.uk) Nature Aging | Volume 6 | February 2026 | 368–392 368 However, the specific SASP factors responsible for these effects remain unknown. Multiple componentsoftheSASP have been identified (including IL-6, IL-1α, CXCL2, MMP-3 and VEGF), but, in different clinical states, the SASPis heterogeneous and dynamic and highly dependent on the inducer, tissue of origin or cell type and even the duration of thesenescent burden12. TGFβ is a pleiotropic cytokine commonly se

FAQs

Why is platinum-based chemotherapy resistance a problem in lung and ovarian cancer?

The study notes that platinum-based treatments remain standard but outcomes are still poor. It highlights that therapy can produce tumor-promoting microenvironment phenotypes, enabling resistance.

What role does cellular senescence and SASP play in resistance?

Cisplatin can induce cellular senescence, leading to a senescence-associated secretory phenotype (SASP). The secreted factors can promote malignant traits in neighboring recipient cells.

How does TGFβ contribute mechanistically, and what intervention is proposed?

The SASP is enriched in TGFβ ligands and activates TGFBR1 through AKT/mTOR signaling, enhancing proliferation and malignant behavior. Inhibition of TGFBR1 with galunisertib reduces tumor progression and tumor burden, and improves survival in models.

Sep 22, 2026

Upload by Levi