Targeting autophagy potentiates antitumor activity of Met-TKIs against Met-amplified gastric cancer
Targeting autophagy potentiates antitumor activity of Met-TKIs against Met-amplified gastric cancer
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靶向自噬增强 Met-TKI 对 Met 扩增胃癌的抗肿瘤活性
DOI：
10.1038/s41419-019-1314-x
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发表时间：
2019-02-13
影响因子：
9
通讯作者：
Shen, Lin
中科院分区：
文献类型：
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作者：
Lin, Xiaoting;Peng, Zhi;Shen, Lin
正在进行临床试验的Met酪氨酸激酶抑制剂（Met- tkis）是治疗Met扩增型胃癌（GC）的一个有希望的选择，但如何优化其抗肿瘤活性，特别是与联合方案仍不清楚。由于已知自噬是由Met-TKIs启动的，我们研究了其潜在机制和Met-TKIs联合自噬抑制剂治疗met扩增GC的治疗潜力。正如预期的那样，四种Met-TKIs诱导met扩增的GC细胞自噬，其特征是p62降解，LC3-II积累和lc3阳性点增加。用联合溶酶体抑制剂巴菲霉素A1 （Baf A1）和羟氯喹（HCQ）进一步验证Met-TKIs对自噬通量的激活作用。分子研究表明，肝细胞生长因子（HGF）和mTOR激动剂MHY1485 （MHY）可以缓解Met- tki治疗诱导的自噬以及mTOR和ULK1的去磷酸化，这表明Met- tki通过Met/mTOR/ULK1级联启动自噬。有趣的是，在met扩增的GC临床前模型中，在自噬阻断存在的情况下，Met-TKIs进一步抑制细胞存活和肿瘤生长。因此，这些发现表明Met/mTOR/ULK1级联负责Met- tki介导的自噬，Met- tki联合自噬抑制剂是治疗Met扩增型GC的有希望的选择。
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.