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Updated: Mar 27, 2026
Generation and Expansion of Primary, Malignant Pleural Mesothelioma Tumor Lines
Published on: April 21, 2022
KAT5 (Tip60) is a potential therapeutic target in malignant pleural mesothelioma
Sian Cregan1, Lauran McDonagh2, Yun Gao1
1Thoracic Oncology Research Group, Institute of Molecular Medicine, St. James's Hospital, Dublin, Ireland.
Abstract:
Malignant pleural mesothelioma (MPM) is a rare aggressive cancer of the pleura. Asbestos exposure (through inhalation) is the most well established risk factor for mesothelioma. The current standard of care for patients suffering from MPM is a combination of cisplatin and pemetrexed (or alternatively cisplatin and raltitrexed). Most patients, however, die within 24 months of diagnosis. New therapies are therefore urgently required for this disease. Lysine acetyltransferases (KATs) including KAT5 have been linked with the development of cisplatin resistance. This gene may therefore be altered in MPM and could represent a novel candidate target for intervention. Using RT-PCR screening the expression of all known KAT5 variants was found to be markedly increased in malignant tumors compared to benign pleura. When separated according to histological subtype, KAT5 was significantly overexpressed in both the sarcomatoid and biphasic subgroups for all transcript variants. A panel of MPM cell lines including the normal pleural cells LP9 and Met5A was screened for expression of KAT5 variants. Treatment of cells with a small molecule inhibitor of KAT5 (MG-149) caused significant inhibition of cellular proliferation (p<0.0001), induction of apoptosis and was accompanied by significant induction of pro-inflammatory cytokines/chemokines.
Insights
Malignant pleural mesothelioma (MPM) exhibits increased KAT5 gene expression, a potential driver of cisplatin resistance. Inhibiting KAT5 with MG-149 suppressed cancer cell growth and induced apoptosis, suggesting a new therapeutic target for this aggressive cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Malignant pleural mesothelioma (MPM) is a rare, aggressive cancer with poor prognosis.
- Current treatments offer limited survival benefits, necessitating novel therapeutic strategies.
- Lysine acetyltransferases (KATs), particularly KAT5, are implicated in cisplatin resistance.
Purpose of the Study:
- To investigate the role of KAT5 gene expression in MPM.
- To evaluate KAT5 as a potential therapeutic target for MPM.
Main Methods:
- RT-PCR screening of KAT5 variants in MPM tumors and benign pleura.
- Analysis of KAT5 expression across MPM histological subtypes.
- In vitro screening of MPM cell lines for KAT5 variants.
- Treatment of MPM cells with a KAT5 inhibitor (MG-149).
Main Results:
- KAT5 variants were markedly overexpressed in MPM tumors compared to benign pleura.
- Significant KAT5 overexpression was observed in sarcomatoid and biphasic MPM subtypes.
- MG-149 treatment significantly inhibited MPM cell proliferation (p<0.0001).
- KAT5 inhibition induced apoptosis and pro-inflammatory cytokines/chemokines in MPM cells.
Conclusions:
- KAT5 is significantly overexpressed in MPM, particularly in aggressive subtypes.
- Targeting KAT5 with inhibitors like MG-149 shows promise for MPM treatment by inhibiting proliferation and inducing apoptosis.
- KAT5 represents a novel therapeutic target for malignant pleural mesothelioma.
