Abstract Met tyrosine kinase inhibitors (Met-TKIs) subjected to ongoing clinical trials are a promising option for Met-amplified gastric cancer (GC), but how to optimize their antitumor activity especially with combination schemes remains unclear. Since autophagy is known to be initiated by Met-TKIs, we investigated its underlying mechanisms and therapeutic potentials of Met-TKIs combined with autophagy inhibitors against Met-amplified GC. As expected, four Met-TKIs induced autophagy in Met-amplified GC cells marked by p62 degradation, LC3-II accumulation and increased LC3-positive puncta. Autophagy flux activation by Met-TKIs was further validated with combined lysosomal inhibitors, bafilomycin A1 (Baf A1) and hydroxychloroquine (HCQ). Molecular investigations reveal that autophagy induction along with mTOR and ULK1 de-phosphorylation upon Met-TKI treatment could be relieved by hepatocyte growth factor (HGF) and mTOR agonist MHY1485 (MHY), suggesting that autophagy was initiated by Met-TKIs via Met/mTOR/ULK1 cascade. Intriguingly, Met-TKIs further suppressed cell survival and tumor growth in the presence of autophagy blockade in Met-amplified GC preclinical models. Thus, these findings indicate Met/mTOR/ULK1 cascade responsible for Met-TKI-mediated autophagy and Met-TKIs combined with autophagy inhibitors as a promising choice to treat Met-amplified GC.

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hepatocyte growth factor hgf mettkis p62 degradation lc3ii accumulation metamplified gastric cancer mtor agonist mhy1485 autophagy inhibitors lysosomal inhibitors bafilomycin a1 baf a1 and hydroxychloroquine met tyrosine kinase inhibitors metamplified gc preclinical ulk1 dephosphorylation lc3positive

Xiaoting Lin,Zhi Peng,Xiaojuan Wang,Jianling Zou,Dongshao Chen,Zuhua Chen,Zhongwu Li,Bin Dong,Jing Gao,Lin Shen,.Targeting autophagy potentiates antitumor activity of Met-TKIs against Met-amplified gastric cancer. 10 (2),.

Xiaoting Lin,Zhi Peng,Xiaojuan Wang,Jianling Zou,Dongshao Chen,Zuhua Chen,Zhongwu Li,Bin Dong,Jing Gao,Lin Shen,"Targeting autophagy potentiates antitumor activity of Met-TKIs against Met-amplified gastric cancer" 10

Xiaoting Lin,Zhi Peng,Xiaojuan Wang,Jianling Zou,Dongshao Chen,Zuhua Chen,Zhongwu Li,Bin Dong,Jing Gao,Lin Shen,"Targeting autophagy potentiates antitumor activity of Met-TKIs against Met-amplified gastric cancer"