Pharmacological inhibition of CDK4/6 impairs diffuse pleural mesothelioma 3D spheroid growth and reduces viability of cisplatin-resistant cells

Our plain-English summary of Pharmacological inhibition of CDK4/6 impairs diffuse pleural mesothelioma 3D spheroid growth and reduces viability of cisplatin-resistant cells, by A. Costa, I.M. Forte, F. Pentimalli, et al (Frontiers in Oncology, 2024).

The study

• Authors: A. Costa, I.M. Forte, F. Pentimalli, C.A. Iannuzzi, L. Alfano, F. Capone, R. Camerlingo, A. Calabrese, C. von Arx, R. Benot Dominguez, M. Quintiliani, M. De Laurentiis, A. Morrione, A. Giordano
• Journal: Frontiers in Oncology
• Published: 2024;14:1418951
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Introduction: Diffuse pleural mesothelioma (DPM) of the pleura is a highly aggressive and treatment-resistant cancer linked to asbestos exposure. Despite multimodal treatment, the prognosis for DPM patients remains very poor, with an average survival of 2 years from diagnosis. Cisplatin, a platinum-based chemotherapy drug, is commonly used in the treatment of DPM. However, the development of resistance to cisplatin significantly limits its effectiveness, highlighting the urgent need for alternative therapeutic strategies. New selective inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) have shown promise in various malignancies by inhibiting cell cycle progression and suppressing tumor growth. Recent studies have indicated the potential of abemaciclib for DPM therapy, and a phase II clinical trial has shown preliminary encouraging results.

Methods: Here, we tested abemaciclib, palbociclib, and ribociclib on a panel of DPM cell lines and non-tumor mesothelial(MET-5A) cells.

Results: Specifically, we focused on abemaciclib, which was the mosteffective cytotoxic agent on all the DPM cell lines tested. Abemaciclib reduced DPM cell viability, clonogenic potential, and ability to grow as three-dimensional (3D) spheroids. In addition, abemaciclib induced prolonged effects, thereby impairing second-generation sphere formation and inducing G0/G1 arrest and apoptosis/ necrosis. Interestingly, single silencing of RB family members did not impair cell response to abemaciclib, suggesting that they likely complement each other in triggering abemaciclib's cytostatic effect. Interestingly, abemaciclib reduced the phosphorylation of AKT, which is hyperactive in DPM and synergized with the pharmacological AKT inhibitor (AKTi VIII). Abemaciclib also synergized with cisplatin and reduced the viability of DPM cells with acquired resistance to cisplatin.

Discussion: Overall, our results suggest that CDK4/6 inhibitors alone or in combination with standard of care should be further explored for DPM therapy.

Copyright © 2024 Costa, Forte, Pentimalli, Iannuzzi, Alfano, Capone, Camerlingo, Calabrese, von Arx, Benot Dominguez, Quintiliani, De Laurentiis, Morrione and Giordano.

In plain English

This laboratory study tested three drugs that block the proteins CDK4 and CDK6 (abemaciclib, palbociclib and ribociclib). They were tested on six diffuse pleural mesothelioma (DPM) cell lines and on immortalized normal mesothelial cells (MET-5A). The study did not look at asbestos exposure or at patients. Abemaciclib had the strongest effect on all the DPM cell lines and did not show comparable toxic effects on MET-5A cells, so the authors focused on it. Abemaciclib reduced colony formation. At 5 micromolar it significantly inhibited the growth of DPM cells as three-dimensional spheroids and their ability to form second-generation spheroids. It produced an increase of approximately 15% in cells in the G0/G1 phase of the cell cycle in two lines. It also induced apoptosis in the DPM lines tested without affecting MET-5A cells. It reduced activation of the protein AKT. Its combinations with cisplatin or with an AKT inhibitor (AKTi VIII) were synergistic in all DPM lines tested. Two cell lines made resistant to cisplatin in the laboratory were sensitive to abemaciclib. The authors concluded that CDK4/6 inhibitors, alone or with standard treatment, should be further explored for DPM therapy.

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 established cell lines, including 3D spheroid cultures; no patients or animals
• Who was studied: Six commercially obtained diffuse pleural mesothelioma cell lines: NCI-H2452, MMB and ISTMES-2 (epithelioid), MSTO-211H (biphasic), NCI-H28 and NCI-H2052 (sarcomatoid). Also MET-5A immortalized normal mesothelial cells. Cisplatin-resistant versions of MSTO-211H and NCI-H2052 were generated in the laboratory.
• Exposure: No asbestos exposure was studied. Cells were treated with the CDK4/6 inhibitors palbociclib, ribociclib and abemaciclib at 1.56 to 50 micromolar for 72 h. Abemaciclib was also tested in combination with cisplatin and with the AKT inhibitor AKTi VIII.
• Main results:
  • Compared with ribociclib and palbociclib, abemaciclib had the highest cytotoxic effect on all DPM cell lines tested. It did not show comparable toxic effects on MET-5A cells.
  • Abemaciclib at IC50 dramatically reduced colony formation in all DPM cell lines tested. MET-5A could not be assessed in this assay.
  • Abemaciclib at 5 micromolar significantly inhibited spheroid formation by four DPM cell lines.
  • After treatment of first-generation spheroids, DPM cells' ability to form second-generation spheroids was significantly inhibited.
  • Abemaciclib increased the proportion of cells in G0/G1 by approximately 15% in NCI-H28 and MSTO-211H, and slightly less in NCI-H2052.
  • Abemaciclib induced apoptosis in all DPM cell lines tested without affecting MET-5A cells.
  • Abemaciclib significantly reduced phosphorylated (active) AKT in all DPM cells.
  • Combinations of abemaciclib with cisplatin or with AKTi VIII gave combination index values below 1 (synergism) in all DPM cell lines tested. The combinations had no toxic effect on MET-5A cells at 72 h.
  • Cisplatin-resistant MSTO-211H and NCI-H2052 cells were sensitive to abemaciclib.
  • Depleting single RB family proteins in MSTO-211H cells did not change their ability to form spheroids. The authors interpreted the results as a functional overlap between RB proteins.
• The authors' conclusion: The authors concluded that CDK4/6 inhibitors, alone or in combination with standard of care, should be further explored for DPM therapy.
• Limitations the authors state:
  • Long-term (clonogenic) effects of abemaciclib could not be assessed in normal MET-5A cells.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Cisplatin, Pleura, Asbestos Exposure, Prognosis, Chemotherapy, Clinical Trial, Apoptosis.

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