New therapeutic targets in pleural mesothelioma: Combined AKT and mTOR inhibition using Ipatasertib and Sapanisertib synergistically inhibits proliferation and viability

Background Targeting aberrantly overexpressed kinases to cure pleural mesothelioma (PM) is a promising therapeutic strategy. The aim of this study was to identify suitable therapy targets by i) detecting recurrent chromosomal gains associated with PM, ii) specific inhibition of amplified and overexpressed kinases in PM cells.

Methods & Materials Primary PM were screened for chromosomal alterations using the OncoScan technology. AKT expression was assessed by immunohistochemistry in primary PM, cell lines, and a patient-derived xenograft (PDX). We then tested the efficacy of the AKT inhibitor Ipatasertib alone and in combination with mTOR inhibitor Sapanisertib in vitro in PM cell lines and primary PM cells. Preclinical evaluation of Ipatasertib and Sapanisertib efficacy was conducted on a PDX selected for simultaneous AKT and mTOR expression.

Results Genomic profiling of 42 primary PM revealed eleven significant gain regions. Among them, 14q32.33 and 19q13.2 gain affected AKT1 and AKT2, two members of the AKT serine/threonine protein kinase family. Protein expression of all three AKT kinases was detected in the majority of 91 PM tumors: 66% PM expressed AKT1, 80% AKT2, 94% AKT3, and 57% PM co-expressed AKT1/AKT2/AKT3. Pan-AKT inhibitor Ipatasertib impaired cell proliferation and viability in three PM cell lines and induced apoptosis. Combined treatment with Ipatasertib and Sapanisertib had a strong synergistic effect in all cell lines and primary cells from two PM patients, even in Cisplatin-resistant cells. We also noted an improved response to the combination in vivo: Ipatasertib alone did not exert significant anti-tumor growth activity on a PM-PDX with co-activated AKT and mTOR, but enhanced the anti-tumor effect of Sapanisertib causing a tumor growth inhibition of 60% vs.44% by Sapanisertib alone.

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

 

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Publikationsverlauf

Artikel online veröffentlicht:
25. August 2025