TY  - EJOU
AU  - Min, Zhiyi 
AU  - Wang, Chunbin 
AU  - Yin, Tongjin 
AU  - Jiao, Wanyan 
AU  - Zhou, Dandan 
AU  - Zhang, Xuyao 
AU  - Cui, Junli 
AU  - Ding, Zhe 

TI  - Autophagy Inhibition Enhances the Antitumor Efficacy of MET Targeting in MET-High Pancreatic Cancer
T2  - Oncology Research

PY  - 
VL  - 
IS  - 
SN  - 1555-3906

AB  - <b>Objectives:</b> MET inhibitors have demonstrated clinical efficacy in several MET-driven malignancies; however, their therapeutic potential in pancreatic cancer remains insufficiently characterized. This study aimed to evaluate the antitumor activity of the selective MET inhibitor savolitinib in MET-high pancreatic cancer and to investigate the role of autophagy in the cellular response to MET inhibition. <b>Methods:</b> MET-high pancreatic cancer cell lines (AsPC-1 and BxPC-3) were treated with savolitinib. Cell viability, apoptosis, transcriptomic profiling, and signaling pathway analyses were performed to characterize its antitumor effects and underlying mechanisms. Autophagy induction was assessed using monodansylcadaverine (MDC) staining, transmission electron microscopy, lysosomal co-localization analysis, and western blotting of autophagy-related markers. The therapeutic efficacy of combining savolitinib with the autophagy inhibitor chloroquine was further evaluated <i>in vitro</i> and in BxPC-3 xenograft models. <b>Results:</b> Savolitinib significantly inhibited MET phosphorylation and reduced the viability of MET-high pancreatic cancer cells while inducing apoptosis, as evidenced by increased levels of cleaved PARP, cleaved caspase-3, and an elevated Bcl-2-associated X protein (Bax)/B-cell lymphoma 2 (Bcl-2) ratio. Transcriptomic analysis revealed significant enrichment of autophagy-related pathways among savolitinib-responsive genes. Savolitinib induced autophagy-associated vesicular changes and autophagic flux, accompanied by suppression of AKT/mTOR signaling. Pharmacological inhibition of autophagy with chloroquine markedly enhanced savolitinib-induced apoptosis <i>in vitro</i> and significantly improved tumor growth inhibition <i>in vivo</i>, achieving a tumor growth inhibition rate of 84.96% in the combination-treatment group without obvious systemic toxicity under the tested conditions. <b>Conclusion:</b> Savolitinib-induced autophagy functions as an adaptive cytoprotective response in MET-high pancreatic cancer. Combined inhibition of MET and autophagy enhances antitumor activity and warrants further evaluation in MET-high pancreatic cancer models.
KW  - Savolitinib; pancreatic cancer; MET; autophagy; combination therapy

DO  - 10.32604/or.2026.084396