Pseudo-senescence induced by palbociclib does not sensitise pleural mesothelioma cells to combinations with senolytics

Our plain-English summary of Pseudo-senescence induced by palbociclib does not sensitise pleural mesothelioma cells to combinations with senolytics, by I. Sreeram, S. Plans-Marin, M. Cruz-Rodríguez, et al (Cell Death & Disease, 2026).

The study

• Authors: I. Sreeram, S. Plans-Marin, M. Cruz-Rodríguez, E. Aliagas, D. Palau-Gallinat, C. Muñoz-Pinedo, E. Nadal
• Journal: Cell Death & Disease
• Published: 2026;17(1)
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Pleural Mesothelioma (PM) is an aggressive neoplasm of the lung pleura with poor survival rates, highlighting the urgent need for novel therapeutic options. The CDK4/6 inhibitors abemaciclib and palbociclib have demonstrated promising results in patient-derived xenograft models of PM. In this study, we observed that palbociclib reduced proliferation, leading to increased cell size, enhanced SA-β-galactosidase activity, and elevated secretion of IL-6 and IL-8 (SASP), all of which are hallmarks of senescence. However, upon drug removal, the cells regrew. To enhance therapeutic efficacy, we attempted to induce cell death in palbociclib-pretreated PM cells with conventional senolytics, such as BH3 mimetics. While some cells showed sensitivity to Bcl-xL inhibitors, neither navitoclax nor the specific Bcl-xL inhibitor A-1331852, nor other BH3 mimetics targeting Bcl-2 (venetoclax) or Mcl-1 (S63845) increased cell death when combined with palbociclib. We explored the activity of signalling pathways after treatment with palbociclib and identified higher Src and STAT3 phosphorylation, as well as activation of the mTORC1 axis. Therefore, we employed inhibitors of these pathways, such as dasatinib, momelotinib or Torin-1, which did not synergise with palbociclib to kill the cells. In contrast, we found that the chemotherapeutic drug cisplatin induces permanent cell cycle arrest and complete senescence in PM cells. While both drugs increased the phosphorylation of γH2AX, the effects of cisplatin were stronger and more consistent across cell lines. The differential effects of palbociclib and cisplatin on permanent growth arrest were verified by sorting PM cells based on size and β-galactosidase activity. Our findings underscore the importance of understanding the nature of therapy-induced senescence when assessing the effectiveness of senolytics in different tumour models.

© 2026. The Author(s).

In plain English

This was a laboratory study of pleural mesothelioma cells grown in dishes. It did not study patients or asbestos exposure. The authors used five commercial mesothelioma cell lines and three lines grown from three patients' pleural fluid. Breast (MCF7) and lung (A549) cancer cells were used for comparison. The cancer drug palbociclib slowed growth and produced features linked to senescence, a lasting non-dividing state: larger cells, more SA-β-galactosidase activity and more inflammatory proteins IL-6 and IL-8. It caused at most 40% cell death at 0.5 µM. After the drug was removed, the mesothelioma cells grew again and mostly lost these features. Alone, the Bcl-xL inhibitors navitoclax and A-1331852 affected all mesothelioma cell lines; adding palbociclib mostly did not significantly increase this, except an apparently additive effect in H28, H2452 and H226. Other combinations showed no significant benefit, apart from a slight effect with venetoclax in MSTO-211H. Cisplatin-treated cells did not resume growth after drug removal. The authors concluded that palbociclib may cause 'pseudo-senescence', which may limit its clinical benefit. Their cell-sorting test was done once per cell line.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) experiments on cancer cell lines
• Who was studied: Five commercial pleural mesothelioma cell lines (MSTO-211H, H28, H226, H2052, H2452). Three primary cell lines (ICO_MPM1, ICO_MPM2, ICO_MPM3) derived from pleural effusions of three patients with pleural mesothelioma. Breast (MCF7) and lung (A549) adenocarcinoma cell lines served as non-mesothelioma comparisons. The work was done at research institutes in L'Hospitalet de Llobregat and Barcelona, Spain.
• Exposure: No asbestos or fiber exposure was studied. The exposures were drugs given to the cells: palbociclib (0.25 to 0.5 µM for 15 days in the long-term experiment), cisplatin (0.5 to 10 µM for 3 days), and combinations of palbociclib with navitoclax, A-1331852, venetoclax, S63845, dasatinib, momelotinib, Torin-1, metformin and MKC8866.
• Main results:
  • Palbociclib suppressed growth of all mesothelioma cell lines, but the cells regrew after the drug was removed.
  • Palbociclib caused a maximum of 40% cell death at 0.5 µM.
  • Palbociclib caused cell enlargement, increased SA-β-galactosidase activity and increased IL-6 and IL-8. The enlarged, senescent-like appearance was lost in most cell lines after drug removal, and cytokine levels dropped.
  • All mesothelioma cell lines were sensitive to the Bcl-xL inhibitors navitoclax and A-1331852 alone. Adding palbociclib at the same time did not significantly enhance this, except in H28, H2452 and H226, where the effect appeared additive.
  • Combining palbociclib with S63845 or venetoclax had no significant effect. The one exception was MSTO-211H, which showed a slightly enhanced effect with venetoclax plus palbociclib.
  • After palbociclib, phosphorylation of Src kinases, STAT3 and mTOR increased. However, dasatinib near its IC50 did not synergise with palbociclib, and combinations with momelotinib or Torin-1 showed no significant antitumour effect.
  • Cells pretreated with cisplatin did not resume growing after the drug was removed.
  • In the cell-sorting experiment, palbociclib-pretreated cells regrew whatever their size or SA-β-galactosidase activity. Almost none of the sorted cisplatin-pretreated populations regrew.
  • Levels of the DNA-damage marker phospho-γH2AX and the cell-cycle-arrest marker p21 were higher with cisplatin than with palbociclib in all cells tested. The exception was p21 in H2452, which neither drug increased. Small increases caused by palbociclib reversed after drug withdrawal.
• The authors' conclusion: The authors concluded that palbociclib's cytostatic effects in these cells were largely reversible. They suggested it may induce 'pseudo-senescence' rather than true senescence, which may ultimately limit the clinical efficacy of CDK4/6 inhibition in mesothelioma. They stressed the need to define the nature of therapy-induced senescence when evaluating senolytic strategies.
• Limitations the authors state:
  • Because of the technical complexity of the cell-sorting assay, only a single biological replicate was reported for each cell line.
  • There are no specific and definitive biomarkers for senescent cells, and SA-β-galactosidase is not exclusive to senescence.
  • In some cell lines, counting cells with high SA-β-galactosidase activity was difficult, possibly because high confluency raised enzyme activity.
  • The first cisplatin experiment used doses above clinically achievable concentrations, which led the authors to repeat it at lower doses.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Neoplasm, Pleura, Cisplatin.

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• Metformin produces growth inhibitory effects in combination with nutlin-3a on malignant mesothelioma through a cross-talk between mTOR and p53 pathways — K. Shimazu, Y. Tada, et al. (2017)
• Combination of a p53-activating CP-31398 and an MDM2 or a FAK inhibitor produces growth suppressive effects in mesothelioma with wild-type p53 genotype — B. Zhong, M. Shingyoji, et al. (2020)
• Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells — M. Bonelli, R. Terenziani, et al. (2020)
• Mitochondria-derived reactive oxygen species drive GANT61-induced mesothelioma cell apoptosis — C.B. Lim, C.M. Prêle, et al. (2015)

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