Abrogating G₂/M checkpoint through WEE1 inhibition in combination with chemotherapy as a promising therapeutic approach for mesothelioma

Our plain-English summary of Abrogating G₂/M checkpoint through WEE1 inhibition in combination with chemotherapy as a promising therapeutic approach for mesothelioma, by P. Indovina, E. Marcelli, D. Di Marzo, et al (Cancer Biology & Therapy, 2014).

The study

• Authors: P. Indovina, E. Marcelli, D. Di Marzo, N. Casini, I.M. Forte, F. Giorgi, L. Alfano, F. Pentimalli, A. Giordano
• Journal: Cancer Biology & Therapy
• Published: 2014;15(4):380-8
• Cited by: 26 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma (MM) is a very aggressive asbestos-related neoplasm of the serous membranes, whose incidence is increasing worldwide. Although the introduction of new drug combinations, such as cisplatin plus pemetrexed/gemcitabine, has determined an improvement in the patient quality of life, MM remains a universally fatal disease. The observation that key G 1/S checkpoint regulators are often functionally inactivated in MM prompted us to test whether the use of G 2/M checkpoint inhibitors, able to sensitize G 1/S checkpoint-defective cancer cells to DNA-damaging agents, could be successful in MM. We treated six MM cell lines, representative of different histotypes (epithelioid, biphasic, and sarcomatoid), with cisplatin in combination with MK-1775, an inhibitor of the G 2/M checkpoint kinase WEE1. We observed that MK-1775 enhanced the cisplatin cytotoxic effect in all MM cell lines, except the sarcomatoid cell line, which is representative of the most aggressive histotype. As expected, the enhancement in cisplatin toxicity was accompanied by a decrease in the inactive phosphorylated form of cyclin-dependent kinase 1 (CDK1), a key substrate of WEE1, which is indicative of G 2/M checkpoint inactivation. Consistently, we also observed a decrease in G 2/M accumulation and an increase in mitotic entry of DNA-damaged cells and apoptosis, probably due to the loss of the cell ability to arrest cell cycle in response to DNA damage, irrespectively of p53 mutational status. Notably, this treatment did not increase cisplatin cytotoxicity on normal cells, thus suggesting a possible use of MK-1775 in combination with cisplatin for a safe and efficient treatment of epithelioid and biphasic MM.

In plain English

This was a laboratory study of mesothelioma cells grown in dishes. It did not involve patients or study asbestos exposure. The authors treated six malignant mesothelioma cell lines, representing the epithelioid, biphasic and sarcomatoid types, with the chemotherapy drug cisplatin (2.5 to 15 μM). Cisplatin was given alone or combined with MK-1775 (150 or 250 nM), an experimental drug that blocks a cell-cycle checkpoint protein called WEE1. MK-1775 increased cisplatin's cell-killing effect in every cell line except the one sarcomatoid line, NCI-H2052. In the lines where the combination worked, the authors reported synergy between the two drugs. In normal human skin fibroblasts, MK-1775 did not significantly increase cisplatin's toxicity. In two responding lines, NCI-H2452 and MSTO-211H, the combination led to more cells entering cell division with damaged DNA, and more programmed cell death (apoptosis), than cisplatin alone. The combination worked in cell lines with and without p53 mutations. The authors concluded that their findings suggest a possible use of MK-1775 with cisplatin for epithelioid and biphasic mesothelioma. They noted it had not yet been tested in animal models of mesothelioma.

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-line experiment
• Who was studied: Six malignant mesothelioma cell lines: epithelioid (IST-MES1, IST-MES2, REN, NCI-H2452), biphasic (MSTO-211H) and sarcomatoid (NCI-H2052). Primary human skin fibroblasts served as normal comparison cells.
• Exposure: Cisplatin at 2.5 to 15 μM, alone or combined with the WEE1 inhibitor MK-1775 at 150 or 250 nM. No asbestos exposure was studied.
• Main results:
  • MK-1775 enhanced cisplatin's cytotoxic effect, in a concentration-dependent manner, in all mesothelioma cell lines except the sarcomatoid line NCI-H2052.
  • Combination index analysis, done only in the cell lines where the combination was effective, showed synergy between cisplatin and MK-1775.
  • In primary human skin fibroblasts, MK-1775 did not significantly enhance cisplatin's cytotoxic effects.
  • Given alone, MK-1775 reduced IST-MES2 cell viability to approximately 65% at 150 nM and 47% at 250 nM (P < 0.05).
  • In all mesothelioma cell lines, the combination reduced the inactive phosphorylated form of CDK1 (phospho-CDK1 Tyr15) compared with cisplatin alone.
  • In NCI-H2452 and MSTO-211H cells, the combination decreased accumulation of cells at the G2/M checkpoint and increased entry into cell division by cells carrying unrepaired DNA damage. This was followed by increased apoptosis.
  • In NCI-H2452 and MSTO-211H cells, caspase-3 activity (a marker of apoptosis) increased significantly with the combination compared with cisplatin alone.
  • The combination was effective in p53 wild-type cell lines (IST-MES1, MSTO-211H) and in p53-mutated cell lines (NCI-H2452, REN, IST-MES2).
• The authors' conclusion: The authors concluded that their findings suggest a possible use of MK-1775 combined with cisplatin for a safe and efficient treatment of epithelioid and biphasic mesothelioma.
• Limitations the authors state:
  • The drug combination had not yet been tested in animal models 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: Chemotherapy, Mesothelioma, Malignant Mesothelioma, Neoplasm, Cisplatin, Pemetrexed (Alimta), Gemcitabine, Quality of Life.

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