Abstract
BackgroundMalignant pleural mesothelioma (MPM) is a highly aggressive cancer with a dismal prognosis. There is increasing interest in targeting chromatin regulatory pathways in difficult-to-treat cancers. In preliminary studies, we found that KDM4A (lysine-specific histone demethylase 4) was overexpressed in MPM.MethodsKDM4A protein expression was determined by immunohistochemistry or immunoblotting. Functional inhibition of KDM4A by targeted knockdown and small molecule drugs was correlated to cell growth using cell lines and a xenograft mouse model. Gene expression profiling was performed to identify KDM4A-dependent signature pathways.ResultsLevels of KDM4A were found to be significantly elevated in MPM patients compared to normal mesothelial tissue. Inhibiting the enzyme activity efficiently reduced cell growth in vitro and reduced tumour growth in vivo. KDM4A inhibitor-induced apoptosis was further enhanced by the BH3 mimetic navitoclax. KDM4A expression was associated with pathways involved in cell growth and DNA repair. Interestingly, inhibitors of the DNA damage and replication checkpoint regulators CHK1 (prexasertib) and WEE1 (adavosertib) within the DNA double-strand break repair pathway, cooperated in the inhibition of cell growth.ConclusionsThe results establish a novel and essential role for KDM4A in growth in preclinical models of MPM and identify potential therapeutic approaches to target KDM4A-dependent vulnerabilities.
Highlights
Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a dismal prognosis
KDM4A expression is essential for cell growth in models of MPM KDM4A levels were evaluated using tissue micro arrays (TMAs), containing a total of 53 MPM and 8 normal pleural tissue specimens from MPM donors
KDM4A protein expression was not detected by IHC in normal mesothelial tissue, but cytoplasmic KDM4A staining was readily found in all MPM tissues (IHC score: 1+: 9.4% (5/53); 2+: 52.8% (28/53); 3+: 37.7% (20/53)) (Fig. 1a)
Summary
Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a dismal prognosis. KDM4A expression was associated with pathways involved in cell growth and DNA repair. CONCLUSIONS: The results establish a novel and essential role for KDM4A in growth in preclinical models of MPM and identify potential therapeutic approaches to target KDM4A-dependent vulnerabilities. MPM can result from exposure to radiation therapy and is occasionally idiopathic.[1] The disease is aggressive and highly malignant with median overall survival of only 8–12 months.[2] MPM tends to cause death by invasive growth of tumour cells and compression of mediastinal structures rather than metastatic growth.[3,4,5] Standard therapy is limited to very few therapeutic options, which have at best 40% response rates. The overall prognosis is dismal and there is a significant need for effective long-term treatments
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