PTEN loss and ERBB2/ERBB3-mediated AKT reactivation drive resistance to MET inhibition in MET-amplified hepatocellular carcinoma.

ABSTRACT:

Background

Hepatocellular carcinoma (HCC) remains a therapeutic challenge due to limited treatment options and frequent resistance to targeted therapies. MET amplification is a promising therapeutic target in a subset of HCC. However, mechanisms of resistance to MET inhibitors are not fully understood, impeding the efficacy of treatments.

Methods

We performed a genome-wide CRISPR-Cas9 screen to identify genetic determinants of resistance to MET inhibitors. The efficacy of selective MET inhibitors, including capmatinib and tepotinib, was evaluated in MET-amplified HCC models. Mechanistic studies were conducted to characterize AKT signaling dynamics and tumour cell responses under various treatment conditions.

Results

MET inhibitors selectively suppressed tumour growth

SUBMITTER: Qian R 

PROVIDER: S-EPMC12698805 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature