Abstract
Malignant pleural mesothelioma is an aggressive cancer, heterogeneous in its presentation and behaviour. Despite an increasing knowledge about molecular markers and their diagnostic and prognostic value, they are not used as much as they might be for treatment allocation. It has been recently reported that mesothelioma cells that lack BAP1 (BRCA1 Associated Protein) are sensitive to inhibition of the EZH2 (Enhancer of Zeste Homolog 2) histone methyltransferase. Since we observed strong H3K27me3 (histone H3 lysine 27 trimetylation) immunoreactivity in BAP1 wild-type mesothelioma biopsies, we decided to characterize in vitro the response/resistance of BAP1 wild-type mesothelioma cells to the EZH2 selective inhibitor, EPZ-6438. Here we demonstrate that BAP1 wild-type mesothelioma cells were rendered sensitive to EPZ-6438 upon SIRT1 (Sirtuin 1) silencing/inhibition or when cultured as multicellular spheroids, in which SIRT1 expression was lower compared to cells grown in monolayers. Notably, treatment of spheroids with EPZ-6438 abolished H3K27me3 and induced the expression of CDKN2A (Cyclin-Dependent Kinase Inhibitor 2A), causing cell growth arrest. EPZ-6438 treatment also resulted in a rapid and sustained induction of the genes encoding HIF2α (Hypoxia Inducible Factor 2α), TG2 (Transglutaminase 2) and IL-6 (Interleukin 6). Loss of CDKN2 is a common event in mesothelioma. CDKN2A silencing in combination with EPZ-6438 treatment induced apoptotic death in mesothelioma spheroids. In a CDKN2A wild-type setting apoptosis was induced by combining EPZ-6438 with 1-155, a TG2 selective and irreversible inhibitor. In conclusion, our data suggests that the expression of CDKN2A predicts cell fate in response to EZH2 inhibition and could potentially stratify tumors likely to undergo apoptosis.
Highlights
Malignant pleural mesothelioma (MPM) is a lethal cancer that originates from the mesothelial cells aligning the pleura [1]
We have described that HIF-2a (Hypoxia Inducible Factor 2a) induces the expression of the H3K27 demethylase KDM6B and reduces the H3K27me3 repressive mark in MPM cells exposed to chronic hypoxia [32]
Recent evidence suggesting the potential efficacy of EZH2 inhibition in preclinical models of BAP1 loss led to a phase II clinical trial evaluating the EZH2 inhibitor Tazemetostat (EPZ-6438) in MPM patients with inactive BAP1 (NCT02860286)
Summary
Malignant pleural mesothelioma (MPM) is a lethal cancer that originates from the mesothelial cells aligning the pleura [1]. The causal association of MPM with asbestos exposure is well established and supported by epidemiological and toxicological studies [2, 3]. Asbestos has been banned in numerous countries, it continues to be used worldwide, and a rise in the MPM global incidence is predicted [4]. The most commonly used chemotherapy drugs for treating MPM include pemetrexed with cisplatin or carboplatin [5]. The high number of non-responders to chemotherapy, as well as the frequent recurrences of the disease [6, 7], suggests the presence of drug-resistant clones within the tumor. Given that MPM develops over many years and its growth rate is in most cases quite low, it is highly likely that it has profound heterogeneity, which makes it challenging to eradicate [8]
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