Not so WEE: targeting G₂/M to kill mesothelioma cells

Our plain-English summary of Not so WEE: targeting G₂/M to kill mesothelioma cells, by P. Dent (Cancer Biology & Therapy, 2014).

The study

• Author: P. Dent
• Journal: Cancer Biology & Therapy
• Published: 2014;15(4):351-2
• Type of article: Comment
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

It has been known for many years that manipulation of cell cycle checkpoint function represents one approach by which the toxicity of chemotherapy and of ionizing radiation can be increased in tumor cells. (1)(-) (3) In particular, abrogation of the G 2/M checkpoint has been shown to enhance the lethality of a wide range of toxic stresses. (1)(-) (3) Inhibition of the G 2/M checkpoint after chemotherapy/irradiation would result in tumor cells entering mitosis with damaged DNA, which would in turn result in loss of clonogenic survival (i.e., a lethal mitosis).

In plain English

This is a short commentary by a single author, not an original study. It discussed a laboratory study by Indovina and colleagues. That study tested whether MK-1775, a drug that blocks an enzyme called WEE1, made malignant mesothelioma cells more sensitive to cisplatin, a standard drug for this cancer. The commentary did not discuss asbestos. As the commentary described it, MK-1775 increased cisplatin's toxicity, in a dose-dependent and synergistic way, in 5 out of 6 mesothelioma cell lines grown in the laboratory. It did not kill non-transformed fibroblasts (non-cancerous cells). This went along with fewer cells stalled at the G2/M checkpoint, the stage just before cell division. MK-1775 forced mesothelioma cells to enter mitosis (begin cell division) even when their DNA was damaged, which the author wrote was likely associated with the increased killing. Cell death was largely apoptotic (programmed cell death). The author noted that the study did not test whether these results carry over to an animal model. Because mesothelioma generally has a poor outcome, the author wrote, it will be of interest to see whether this combination is tested in the clinic.

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: commentary on a laboratory (in vitro, cell culture) study by Indovina et al.; not original research by this author
• Who was studied: in the study discussed: 6 malignant mesothelioma cell lines and non-transformed fibroblasts grown in the laboratory (site of mesothelioma not stated)
• Exposure: no asbestos exposure was studied; the study discussed tested the WEE1 inhibitor drug MK-1775 combined with the chemotherapy drug cisplatin
• Main results:
  • as reported in the commentary, MK-1775 enhanced cisplatin toxicity, dose-dependently and synergistically, in 5 of 6 mesothelioma cell lines and did not kill non-transformed fibroblasts
  • the effect correlated with fewer mesothelioma cells stalled in the G2/M phase after cisplatin treatment
  • MK-1775 forced mesothelioma cells to enter mitosis (begin cell division) regardless of DNA damage, which the author described as likely associated with the enhanced killing
  • cell killing was largely apoptotic and was associated with enhanced caspase 3 activity
• The authors' conclusion: The author wrote that, because mesothelioma generally has a poor outcome, it will be of interest to see whether this drug combination is tested in the clinic
• Limitations the authors state:
  • the author noted that the study discussed did not determine whether the laboratory results translate into an animal model of mesothelioma

Topics

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

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

Related studies

• Abrogating G₂/M checkpoint through WEE1 inhibition in combination with chemotherapy as a promising therapeutic approach for mesothelioma — P. Indovina, E. Marcelli, et al. (2014)
• Pharmacological Inhibition of WEE1 Potentiates the Antitumoral Effect of the dl922-947 Oncolytic Virus in Malignant Mesothelioma Cell Lines — C.A. Iannuzzi, P. Indovina, et al. (2020)
• CRISPR Screening Identifies WEE1 as a Combination Target for Standard Chemotherapy in Malignant Pleural Mesothelioma — D. Xu, S.Q. Liang, et al. (2020)
• Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells — M. Yamaji, A. Ota, et al. (2017)
• FISH Analysis of Crizotinib Target Genes ROS1/ALK/MET in Malignant Mesothelioma — S. Salvi, S. Varesano, et al. (2017)
• Significance of cell proliferation markers (Minichromosome maintenance protein 7, topoisomerase IIalpha and Ki-67) in cavital fluid cytology: can we differentiate reactive mesothelial cells from malignant cells? — F. Kimura, J. Kawamura, et al. (2010)

Browse more research in Cancer Biology & Therapy, or return to medical research.