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

• Published in: Cell death discovery Vol. 9; no. 1; p. 257
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Springer Nature B.V 21.07.2023; Nature Publishing Group UK; Nature Publishing Group
• Subjects: Antineoplastic drugs; Antitumor agents; BRCA1 protein; Ca2+/calmodulin-dependent protein kinase II; Calmodulin; Cisplatin; DNA microarrays; Drug development; Kinases; Malignancy; Mesothelioma; Therapeutic targets
• ISSN: 2058-7716; 2058-7716
• DOI: 10.1038/s41420-023-01552-5

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.