Targeting mTORC2-dependent AKT/FOXO1/RNF125 signaling exploits a therapeutic vulnerability in c-MET-activated and...

Area of Science:

• Hepatocellular Carcinoma Research
• Molecular Oncology
• Signal Transduction Pathways

Background:

• Approximately 10% of human hepatocellular carcinomas (HCC) feature concurrent c-MET activation and β-catenin gain-of-function mutations.
• This specific HCC subtype presents a unique clinical and molecular profile requiring targeted investigation.

Purpose of the Study:

• To investigate the role of the mTORC2/AKT signaling pathway in c-MET-activated/β-catenin-mutated HCC.
• To identify potential therapeutic targets within this signaling cascade.

Main Methods:

• Examined mTORC2/AKT cascade activation in HCC lesions.
• Utilized genetic ablation of Rictor (mTORC2 subunit) to assess its role in hepatocarcinogenesis.
• Investigated downstream effectors including TSC2/mTORC1 and FOXO1 transcription factors.
• Identified and analyzed the role of RNF125 as a transcriptional target of FOXO1.
• Employed an in vivo doxycycline-inducible system to evaluate RNF125's therapeutic potential.

Main Results:

• The mTORC2/AKT cascade was activated in c-Met/β-cateninΔ90 HCC.
• Rictor ablation significantly suppressed c-Met/β-cateninΔ90-dependent hepatocarcinogenesis.
• FOXO1 transcription factors and the TSC2/mTORC1 axis were identified as critical downstream effectors of mTORC2/AKT.
• RNF125, a FOXO1 target, inhibited tumorigenesis and liver cancer cell growth.
• Inducing RNF125 in established HCC suppressed tumor progression.

Conclusions:

• The mTORC2/AKT/FOXO1/RNF125 axis is a critical driver and therapeutic vulnerability in c-MET-activated/β-catenin-mutated HCC.
• FOXO1 plays a tumor-suppressive role specifically in this HCC subtype.
• RNF125 emerges as a promising therapeutic target for this aggressive form of liver cancer.