title: Abrogating G₂/M checkpoint through WEE1 inhibition in combination with chemotherapy as a promising therapeutic approach for mesothelioma.
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.
authors.affiliation: Department of Medicine, Surgery and Neuroscience; University of Siena and Istituto Toscano Tumori (ITT); Siena, Italy; Sbarro Institute for Cancer Research and Molecular Medicine; Center for Biotechnology; College of Science and Technology; Temple University; Philadelphia, PA USA.
authors.forename: Paola
authors.initials: P
authors.lastname: Indovina
authors.affiliation: Department of Medicine, Surgery and Neuroscience; University of Siena and Istituto Toscano Tumori (ITT); Siena, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Marcelli
authors.affiliation: Oncology Research Center of Mercogliano (CROM); Istituto Nazionale Tumori "Fondazione Giovanni Pascale"; IRCCS; Naples, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Di Marzo
authors.affiliation: Department of Medicine, Surgery and Neuroscience; University of Siena and Istituto Toscano Tumori (ITT); Siena, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Casini
authors.affiliation: Oncology Research Center of Mercogliano (CROM); Istituto Nazionale Tumori "Fondazione Giovanni Pascale"; IRCCS; Naples, Italy.
authors.forename: Iris Maria
authors.initials: IM
authors.lastname: Forte
authors.affiliation: Department of Medicine, Surgery and Neuroscience; University of Siena and Istituto Toscano Tumori (ITT); Siena, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Giorgi
authors.affiliation: Oncology Research Center of Mercogliano (CROM); Istituto Nazionale Tumori "Fondazione Giovanni Pascale"; IRCCS; Naples, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Alfano
authors.affiliation: Oncology Research Center of Mercogliano (CROM); Istituto Nazionale Tumori "Fondazione Giovanni Pascale"; IRCCS; Naples, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Pentimalli
authors.affiliation: Department of Medicine, Surgery and Neuroscience; University of Siena and Istituto Toscano Tumori (ITT); Siena, Italy; Sbarro Institute for Cancer Research and Molecular Medicine; Center for Biotechnology; College of Science and Technology; Temple University; Philadelphia, PA USA; Oncology Research Center of Mercogliano (CROM); Istituto Nazionale Tumori "Fondazione Giovanni Pascale"; IRCCS; Naples, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004357:Drug Synergism; D059565:G2 Phase Cell Cycle Checkpoints; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008654:Mesothelioma / Q000188:drug therapy* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011744:Pyrimidinones
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C549567:adavosertib; D002945:Cisplatin
keywords: CDK1; G2/M checkpoint; MK-1775; WEE1; apoptosis; cisplatin; mesothelioma