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

Apr 10, 2026Cell death & disease

Palbociclib-induced aging-like state does not make pleural mesothelioma cells more sensitive to senolytic drug combinations

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗OA ↗

Abstract

Palbociclib reduced proliferation in pleural mesothelioma cells but did not induce permanent cell death.

Palbociclib led to increased cell size, enhanced senescence-associated enzyme activity, and elevated secretion of inflammatory markers IL-6 and IL-8.
Upon removal of palbociclib, pleural mesothelioma cells regrew, indicating a lack of permanent growth arrest.
Cisplatin was found to induce complete senescence and permanent cell cycle arrest in pleural mesothelioma cells.
Phosphorylation levels of γH2AX were increased by both palbociclib and cisplatin, but cisplatin's effects were stronger and more consistent across different cell lines.
Inhibitors targeting signaling pathways activated by palbociclib did not enhance cell death when combined with the drug.

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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.

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

Abstract

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