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

[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 in MET-amplified HCC. However, PTEN deficiency sustained AKT activation despite MET blockade, facilitating tumour survival. Moreover, MET inhibitor treatment triggered adaptive upregulation of ERBB2/ERBB3, leading to AKT reactivation and resistance. Combined inhibition of MET and AKT or ERBB kinases synergistically restored therapeutic response and induced apoptosis. These resistance mechanisms also reduced the efficacy of cabozantinib. Notably, neither combination was effective in MET-high non-amplified HCC.

[CONCLUSION] Our study identifies PTEN deficiency and ERBB2/ERBB3-mediated reactivation as key resistance mechanisms to MET inhibition in MET-amplified HCC. The findings support biomarker-informed combination strategies and underscore the importance of stratifying patients based on MET amplification status.