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CAMK2D: a novel molecular target for BAP1-deficient malignant mesothelioma

Malignant mesothelioma (MMe) is a rare but aggressive malignancy. Although the molecular genetics of MMe is known, including BRCA1-associated protein-1 (BAP1) gene alterations, the prognosis of MMe patients remains poor. Here, we generated BAP1 knockout (BAP1-KO) human mesothelial cell clones to dev...

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Detalles Bibliográficos
Autores principales: Karnan, Sivasundaram, Ota, Akinobu, Murakami, Hideki, Rahman, Md. Lutfur, Wahiduzzaman, Md, Hasan, Muhammad Nazmul, Vu, Lam Quang, Hanamura, Ichiro, Inoko, Akihito, Riku, Miho, Ito, Hideaki, Kaneko, Yoshifumi, Hyodo, Toshinori, Konishi, Hiroyuki, Tsuzuki, Shinobu, Hosokawa, Yoshitaka
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10362017/
https://www.ncbi.nlm.nih.gov/pubmed/37479714
http://dx.doi.org/10.1038/s41420-023-01552-5
Descripción
Sumario:Malignant mesothelioma (MMe) is a rare but aggressive malignancy. Although the molecular genetics of MMe is known, including BRCA1-associated protein-1 (BAP1) gene alterations, the prognosis of MMe patients remains poor. Here, we generated BAP1 knockout (BAP1-KO) human mesothelial cell clones to develop molecular-targeted therapeutics based on genetic alterations in MMe. cDNA microarray and quantitative RT-PCR (qRT-PCR) analyses revealed high expression of a calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D) gene in the BAP1-KO cells. CAMK2D was highly expressed in 70% of the human MMe tissues (56/80) and correlated with the loss of BAP1 expression, making it a potential diagnostic and therapeutic target for BAP1-deficient MMe. We screened an anticancer drugs library using BAP1-KO cells and successfully identified a CaMKII inhibitor, KN-93, which displayed a more potent and selective antiproliferative effect against BAP1-deficient cells than cisplatin or pemetrexed. KN-93 significantly suppressed the tumor growth in mice xenografted with BAP1-deficient MMe cells. This study is the first to provide a potential molecular-targeted therapeutic approach for BAP1-deficient MMe.