CDK4/6 Inhibition Enhances the Efficacy of Standard Chemotherapy Treatment in Malignant Pleural Mesothelioma Cells

Our plain-English summary of CDK4/6 Inhibition Enhances the Efficacy of Standard Chemotherapy Treatment in Malignant Pleural Mesothelioma Cells, by R. Terenziani, M. Galetti, S. La Monica, et al (Cancers, 2022).

The study

• Authors: R. Terenziani, M. Galetti, S. La Monica, C. Fumarola, S. Zoppi, R. Alfieri, G. Digiacomo, A. Cavazzoni, D. Cavallo, M. Corradi, M. Tiseo, P.G. Petronini, M. Bonelli
• Journal: Cancers
• Published: 2022;14(23)
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: The loss of the CDKN2A/ARF (cyclin-dependent kinase inhibitor 2A/alternative reading frame) gene is the most common alteration in malignant pleural mesothelioma (MPM), with an incidence of about 70%, thus representing a novel target for mesothelioma treatment. In the present study, we evaluated the antitumor potential of combining the standard chemotherapy regimen used for unresectable MPM with the CDK4/6 (cyclin-dependent kinase 4 or 6) inhibitor abemaciclib.

Methods: Cell viability, cell death, senescence, and autophagy induction were evaluated in two MPM cell lines and in a primary MPM cell culture.

Results: The simultaneous treatment of abemaciclib with cisplatin and pemetrexed showed a greater antiproliferative effect than chemotherapy alone, both in MPM cell lines and in primary cells. This combined treatment induced cellular senescence or autophagic cell death, depending on the cell type. More in detail, the induction of cellular senescence was related to the increased expression of p21, whereas autophagy induction was due to the impairment of the AKT/mTOR signaling. Notably, the effect of the combination was irreversible and no resumption in tumor cell proliferation was observed after drug withdrawal.

Conclusion: Our results demonstrated the therapeutic potential of CDK4/6 inhibitors in combination with chemotherapy for the treatment of MPM and are consistent with the recent positive results in the MiST2 arm in abemaciclib-treated patients.

In plain English

This was a laboratory study of malignant pleural mesothelioma (MPM) cells. No patients were treated, and asbestos exposure was not studied. The authors tested the CDK4/6 inhibitor abemaciclib with the standard chemotherapy drugs cisplatin and pemetrexed, with the chemotherapy at low concentrations. They used two commercial MPM cell lines (MSTO-211H and H28) and cells (ZS-LP) from one 66-year-old male patient. Giving all three drugs at once inhibited cell growth more than abemaciclib alone, chemotherapy alone, or sequential schedules. The combined effect was synergistic in MSTO-211H and H28 cells and additive in ZS-LP cells. With all three drugs, 70% of MSTO-211H and 60% of ZS-LP cells entered senescence, a non-dividing state, while cell death rose only 10 to 15%. H28 cells showed no senescence; instead they showed autophagy and more than 30% cell death. In MSTO-211H and H28 cells, the growth inhibition from the combination persisted after the drugs were removed, whereas cells given chemotherapy alone resumed growing. The authors concluded that their preclinical data support clinical evaluation of abemaciclib with cisplatin plus pemetrexed in p16INK4a-negative patients.

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) cell culture experiment
• Who was studied: Two commercial human MPM cell lines, MSTO-211H (biphasic) and H28 (epithelioid), plus a primary cell line (ZS-LP) obtained from the pleural effusion of one male patient, aged 66, with biphasic mesothelioma, stage T4 N0
• Exposure: Drug treatments, not asbestos. Cells received abemaciclib, cisplatin and pemetrexed, alone or combined, given simultaneously for 72 h or in sequential schedules. Doses were abemaciclib 0.5 µM, cisplatin 0.3 µM and pemetrexed 0.02 µM in MSTO-211H cells, and 1 µM, 1 µM and 0.05 µM in H28 and ZS-LP cells. The chemotherapy drugs were used at sub-IC50 concentrations.
• Main results:
  • In all three cell models, simultaneous treatment with abemaciclib and chemotherapy inhibited cell proliferation more strongly than abemaciclib alone, chemotherapy alone, or the sequential treatments.
  • The drug interaction was synergistic in MSTO-211H and H28 cells and additive in ZS-LP cells.
  • In MSTO-211H and ZS-LP cells, simultaneous treatment produced only a slight increase in cell death, ranging from 10 to 15%.
  • In H28 cells, cell death reached more than 30% with abemaciclib plus both cisplatin and pemetrexed.
  • After triple-drug treatment, 70% of MSTO-211H cells and 60% of ZS-LP cells were senescent. With abemaciclib alone the figures were around 40% and 30%.
  • H28 cells showed no senescence with abemaciclib alone or combined with chemotherapy; instead, the treatment induced autophagy in H28 cells.
  • In colony formation experiments, MSTO-211H and H28 cells were treated for 6 days and then given 6 drug-free days. Cells treated with cisplatin and pemetrexed, alone or together, restored their proliferation after drug withdrawal.
  • In MSTO-211H cells, abemaciclib alone did not have an irreversible effect, but its combination with chemotherapy maintained growth inhibition after drug removal. In H28 cells, abemaciclib alone inhibited proliferation irreversibly.
• The authors' conclusion: The authors concluded that their preclinical data support the ongoing clinical evaluation of abemaciclib in p16INK4a-negative patients, in particular in combination with cisplatin plus pemetrexed.

Topics

Medical terms in this study, explained in our Lexicon: Chemotherapy, Pleural Mesothelioma, CDKN2A, Mesothelioma, Unresectable, Cisplatin, Pemetrexed (Alimta).

Related studies

• Dual Inhibition of CDK4/6 and PI3K/AKT/mTOR Signaling Impairs Energy Metabolism in MPM Cancer Cells — M. Bonelli, R. Terenziani, et al. (2020)
• MTH1 Inhibition Alleviates Immune Suppression and Enhances the Efficacy of Anti-PD-L1 Immunotherapy in Experimental Mesothelioma — S.F. Magkouta, P.C. Vaitsi, et al. (2023)
• Strategic selection of MDM2 inhibitors enhances the efficacy of FAK inhibition in mesothelioma based on TP53 genotype — X. Ning, T.T.T. Nguyễn, et al. (2026)
• Synergistic anti-tumor efficacy of immunogenic adenovirus ONCOS-102 (Ad5/3-D24-GM-CSF) and standard of care chemotherapy in preclinical mesothelioma model — L. Kuryk, E. Haavisto, et al. (2016)
• Combined use of irinotecan and p53 activator enhances growth inhibition of mesothelioma cells — B. Han, H.C. Lee-Okada, et al. (2020)
• Inhibition of YB-1 phosphorylation enhances cisplatin activity and disrupts cell division in pleural mesothelioma — K. Schelch, N. Maach, et al. (2025)

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