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 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.