Targeting autophagy potentiates antitumor activity of Met-TKIs against Met-amplified gastric cancer

Xiaoting Lin,Zhongwu Li,Jianling Zou,Bin Dong,Lin Shen,Xiaojuan Wang,Jing Gao,Zhi Peng,Zuhua Chen,Dongshao Chen

doi:10.1038/s41419-019-1314-x

Xiaoting Lin, Zhongwu Li + Show 8 more

Open Access

https://doi.org/10.1038/s41419-019-1314-x

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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.

Highlights

Despite recent improvements in anticancer therapeutics, clinically available drugs for gastric cancer (GC) are limited, and GC remains a leading cause of mortality in China[1]
Regarding GC, a previous study roughly revealed that targeting autophagy initiated by Met-TKIs improved MetTKI efficacy in vitro[23]; Met-TKI-associated autophagy flux alterations, mechanisms underlying autophagy induced by Met-TKIs and therapeutic potentials of dual targeting Met/autophagy in Met-amplified GC, especially in vivo, remain far from clear
LC3-II accumulates due to either increased autophagy flux or decreased autophagy degradation, which can be distinguished with combined lysosomal inhibitors[26]

Summary

Introduction

Despite recent improvements in anticancer therapeutics, clinically available drugs for gastric cancer (GC) are limited, and GC remains a leading cause of mortality in China[1]. Lin et al Cell Death and Disease (2019)10:139 accumulating data, autophagy is frequently induced by drug exposure and acts as an attractive molecular target to potentiate efficacy of anticancer treatment[9,10,11,12,13,14,15,16,17,18,19]. Regarding GC, a previous study roughly revealed that targeting autophagy initiated by Met-TKIs improved MetTKI efficacy in vitro[23]; Met-TKI-associated autophagy flux alterations, mechanisms underlying autophagy induced by Met-TKIs and therapeutic potentials of dual targeting Met/autophagy in Met-amplified GC, especially in vivo, remain far from clear.

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