Genome-wide copy number analysis identifies AKT as a novel therapeutic target in pleural mesothelioma.

PURPOSE: Targeting aberrantly activated kinases in pleural mesothelioma (PM) is a promising therapeutic strategy. To identify potential candidates, we characterized recurrent chromosomal gains in PM and subsequently evaluated the specific inhibition of kinases that were activated by amplification and/or overexpression.

METHODS: 42 primary PM were screened for chromosomal alterations using OncoScan technology and AKT expression was assessed using immunohistochemistry. The impact of Ipatasertib (pan-AKT inhibitor) and Sapanisertib (mTOR inhibitor) on cell survival, apoptosis induction, AKT/mTOR signaling, glycolysis was investigated in cell lines and primary cells. Preclinical anti-tumor efficacy was further assessed in a PDX model selected for AKT and mTOR expression.

RESULTS: OncoScan profiling identified eleven regions of significant chromosomal gains. Among them, 14q32.33 and 19q13.2 gains affected AKT1 and AKT2, members of the AKT serine/threonine protein kinase family. AKT1 protein was expressed in 66 % (60/91), AKT2 in 80 % (73/91) and AKT3 in 94 % (86/91) PM. 57 % PM co-expressed AKT1/AKT2/AKT3. Treatment with Ipatasertib impaired cell viability in PM cell lines and induced apoptosis. Combined treatment with Ipatasertib and Sapanisertib had a synergistic cytotoxic effect in all three cell lines and primary cells from two PM patients, even in Cisplatin-resistant cells. We also noted an improved response to the combination in a PDX model. Mechanistically, the combined treatment acted synergistically to inactivate AKT/mTOR downstream signaling, suppress glycolysis, and trigger ATP depletion.

CONCLUSIONS: Our study demonstrates recurrent activation of AKT kinases by copy number gains and upregulated expression in PM. Pharmacological AKT and mTOR inhibition is a promising therapeutic alternative for mesothelioma.