Evidence map›Paper›PMID 40991144›Full record

ArticleCellular oncology (Dordrecht, Netherlands)2025

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

Ruolan Qian, Yuchen Guo, Xiaolin Hu, Jing Ling, Haigang Geng, Qiaoqiao Ye, Linmeng Zhang, Shujie Zhan, Long Liao, Yang Ge and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cellular oncology (Dordrecht, Netherlands), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors.

Ruolan Qian *State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Yuchen Guo *Medical Center on Aging of Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Xiaolin Hu *School of Public Health, Center for Single-cell Omics, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China.
Jing LingDepartment of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Haigang GengDepartment of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Qiaoqiao YeState Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Linmeng ZhangState Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shujie ZhanState Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Long LiaoState Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Yang GeSchool of Public Health, Center for Single-cell Omics, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China. geyang19861026@icloud.com.
Quan ZhengSchool of Public Health, Center for Single-cell Omics, Shanghai Jiao Tong University School of Medicine, Shanghai, P. R. China. tczq0236@sjtu.edu.cn.
Ying CaoState Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. ycao@shsci.org.

Funding

Key laboratory of the Ministry of Education Foundation SHSMU-ZLCX20211602National Natural Science Foundation of China 81902673National Natural Science Foundation of China 82102923National Natural Science Foundation of China 82303948Shanghai Jiao Tong University Foundation 24X010301428Shanghai Municipal Health Commission 2022YQ071
6 · The paper itself

Abstract

backgroundHepatocellular 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.

methodsWe 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.

resultsMET 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.

conclusionOur 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.

Indexed as

Carcinoma, HepatocellularDrug Resistance, NeoplasmErb-b2 Receptor Tyrosine KinasesLiver NeoplasmsProto-Oncogene Proteins c-aktProto-Oncogene Proteins c-metPTEN PhosphohydrolaseReceptor, ErbB-3AnimalsApoptosisCell Line, TumorGene AmplificationHumansProtein Kinase InhibitorsSignal TransductionERBB2 protein, humanErb-b2 Receptor Tyrosine KinasesERBB3 protein, humanMET protein, humanProtein Kinase InhibitorsProto-Oncogene Proteins c-aktProto-Oncogene Proteins c-metPTEN PhosphohydrolasePTEN protein, humanReceptor, ErbB-3AKT signaling axisERBB receptor kinasesHepatocellular carcinomaMET inhibitorTherapeutic resistance

Identifiers

PMID40991144
PMCPMC12698805

What OpenQuestion holds

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LicenceCC BY-NC-ND
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.