Multicenter preclinical study identifies AKT as a novel therapeutic target in pleural mesothelioma

Targeting aberrantly activated kinases in pleural mesothelioma (PM) is a promising therapeutic strategy. A multicenter preclinical study in Germany characterized recurrent chromosomal gains in PM and subsequently evaluated the specific inhibition of kinases that were activated by amplification and/or overexpression. A total of 42 primary PM were screened for chromosomal alterations using OncoScan technology, and AKT expression was assessed using immunohistochemistry. OncoScan profiling identified eleven regions of significant chromosomal gain. Among them,14q32.33 and 19q13.2 gains affected AKT1 and AKT2. AKT1 protein was expressed in 66%, AKT2 in 80%, and AKT3 in 94%, while 57% co-expressed AKT1/AKT2/AKT3. Treatment with the pan-AKT inhibitor ipatasertib impaired cell viability in PM cell lines and induced apoptosis. Combined treatment with ipatasertib and the mTOR inhibitor sapanisertib had a synergistic cytotoxic effect in all three cell lines and primary PM cells from two patients, even in cisplatin-resistant cells. The authors observed response of the combination in a PDX model. The authors conclude that the study demonstrates recurrent activation of AKT kinases by copy number gains and upregulated expression in PM.