Cyclin dependent kinase 4 and 6 inhibitors as novel therapeutic agents for targeted treatment of malignant mesothelioma

Our plain-English summary of Cyclin dependent kinase 4 and 6 inhibitors as novel therapeutic agents for targeted treatment of malignant mesothelioma, by N. Sobhani, S.P. Corona, F. Zanconati, et al (Genes & Cancer, 2017).

The study

• Authors: N. Sobhani, S.P. Corona, F. Zanconati, D. Generali
• Journal: Genes & Cancer
• Published: 2017;8(3-4):495-496
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant Mesothelioma (MM) is a rare and aggressive form of tumour that affects the lining of the internal organs for which current treatments have not been proven to be very effective. P16INK4A tumour suppressor encoding CDKN2A gene is often downregulated in MM. This protein is a cyclin dependent kinase 4 and 6 inhibitor, that normally phosphorylates RB1, which has to be un-phosphorylated in order to block cell-cycle at G1 in normal cells. Adding CDK inhibitor molecules to MM in pre-clinical studies has been proven to restore the normal function of p16INK4A, blocking thereby MM cell cycle at G1. Future randomised phase III studies with CDK4/6 inhibitors in MM carrying relevant CDK4/6, cyclin D1/3 or p16 aberrations will be warranted.

In plain English

This two-page commentary reported no patients, experiments or data of its own. The authors discussed published research on drugs blocking cyclin-dependent kinases 4 and 6 (CDK4/6), cell-cycle enzymes, as a possible treatment for malignant mesothelioma. Asbestos appeared only as background: the authors wrote that this cancer is particularly common in regions with historical asbestos exposure, and that registry data placed Trieste among high-incidence regions. They noted that the CDKN2A gene and its protein, p16, are often down-regulated in mesothelioma. They cited two studies finding deletions of the 9p21 region, which contains CDKN2A and CDKN2B, in 52.2% and 45% of pleural mesotheliomas. They described other researchers' work in which a p16-based peptide halted the cell cycle of three mesothelioma cell lines, followed by cell death. They also described xenograft (implanted-tumour) tests and a patent in which new CDK4/6 inhibitors stopped three mesothelioma cell lines multiplying. They mentioned a phase II ribociclib trial designed for solid tumours, including mesotheliomas with relevant CDK4/6, cyclin D1/3 or p16 aberrations. The authors concluded that randomized phase III trials were needed, guided by the tumour's molecular features.

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: Short commentary (narrative overview of published laboratory and clinical research); no original data
• Who was studied: No study population of its own. The authors discussed published genetic, laboratory, animal-model and clinical studies of malignant mesothelioma.
• Exposure: The article did not study an exposure. Asbestos was mentioned only as background. The authors wrote that mesothelioma is particularly common in regions with historical asbestos exposure. Separately, they wrote that Italian tumour registry data placed the Trieste area among 'high incidence' regions. The article's subject was CDK4/6 inhibitor drugs (for example palbociclib, ribociclib) and p16-mimicking molecules.
• Main results:
  • The authors stated that CDKN2A and its protein p16 are often down-regulated in malignant mesothelioma.
  • Cited by the authors (not their own finding): two earlier studies found deletions in the 9p21 region, which contains the CDKN2A and CDKN2B genes, in 52.2% and 45% of pleural mesotheliomas.
  • Cited by the authors: Jennings et al. reported a direct correlation between p16 protein levels and response to chemotherapy, and therefore survival, in patients with mesothelioma.
  • Cited by the authors: in work by Frizelle et al., a p16 peptide (TAT-p16) in three mesothelioma cell lines (H2452, H2052 and H2461) led to cell cycle arrest at G1, followed by cell death. In xenografts of the p16-deficient cell line H2373, it decreased CDK4/6 activity.
  • Cited by the authors: a patent reported that new CDK4/6 inhibitors stopped proliferation of three mesothelioma cell lines (MSTO-211, NCI-H2052, NCI-H28) in the laboratory, with cytostatic activity in the micromolar range.
  • The authors noted that a phase II trial had been designed to evaluate ribociclib in solid tumours, including mesothelioma with relevant CDK4/6, cyclin D1/3 or p16 aberrations (NCT02187783).
• The authors' conclusion: The authors concluded that randomized phase III trials were needed to test CDK4/6 inhibitors, alone or in combination, in malignant mesothelioma, based on the tumour's molecular characteristics. They wrote that selecting patients by these molecular features would be paramount to the success of such trials.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, CDKN2A.

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