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

Claudia Kalla1, Dina Mönch2, Sophia Steinlein1

  • 1Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany; Department of Clinical Pathology, Robert Bosch Hospital 70376 Stuttgart, Germany; Department of Clinical Pharmacology, University Hospital, University of Tübingen 72076 Tübingen, Germany.

Lung Cancer (Amsterdam, Netherlands)
|June 30, 2026
PubMed
Abstract

Insights

Targeting AKT and mTOR kinases shows promise for pleural mesothelioma (PM) treatment. Combining AKT and mTOR inhibitors synergistically reduced cancer cell viability and tumor growth in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Pleural mesothelioma (PM) is a rare and aggressive cancer.
  • Aberrant kinase activation is a key driver in PM pathogenesis.
  • Targeting these kinases offers a potential therapeutic strategy.

Purpose of the Study:

  • To identify recurrent chromosomal gains in PM.
  • To evaluate the impact of inhibiting kinases activated by amplification or overexpression.
  • To assess the therapeutic potential of AKT and mTOR inhibition in PM.

Main Methods:

  • Chromosomal alterations in 42 primary PM samples were analyzed using OncoScan.
  • AKT expression was assessed via immunohistochemistry.
  • The effects of Ipatasertib (pan-AKT inhibitor) and Sapanisertib (mTOR inhibitor) were evaluated in cell lines, primary cells, and a PDX model.

Main Results:

  • Recurrent chromosomal gains, including those affecting AKT1 and AKT2, were identified.
  • High expression of AKT kinases was observed in PM samples.
  • Combined Ipatasertib and Sapanisertib treatment demonstrated synergistic cytotoxicity and anti-tumor efficacy, even in resistant cells, by inhibiting AKT/mTOR signaling and glycolysis.

Conclusions:

  • Recurrent activation of AKT kinases through copy number gains and overexpression is demonstrated in PM.
  • Pharmacological inhibition of AKT and mTOR represents a promising therapeutic approach for mesothelioma.
Keywords:
AKTIpatasertibOncoScan CNV analysisPleural mesotheliomaSapanisertib

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