Inhibition of Autophagy Enhances the antitumor efficacy of Savolitinib in MET-High Pancreatic Cancer

Savolitinib, a potent and selective MET inhibitor, has been approved for the treatment of several MET-driven cancers, including non-small cell lung cancer and gastric cancer. However, its therapeutic potential in pancreatic cancer, a highly lethal malignancy with limited treatment options, remains to be systematically investigated. Given the frequent overexpression of MET in pancreatic tumors, we evaluated the anti-tumor activity of savolitinib, it exhibits potent anti-tumor activity in MET-high human pancreatic cancer cells (AsPC-1 and BxPC-3), by inhibiting MET phosphorylation and activating the apoptotic pathway, as evidenced by increased levels of cleaved PARP and cleaved caspase-3, along with an elevated Bax/Bcl-2 ratio. Transcriptomic profiling of AsPC-1 cells followed by pathway analysis demonstrated that savolitinib-induced differentially expressed genes were significantly enriched in autophagy-related pathways. We confirmed that savolitinib-induced autophagy was mediated through the inhibition of AKT/mTOR signaling. Importantly, autophagy serves as a cytoprotective mechanism, pharmacological inhibition of autophagy by chloroquine synergistically enhanced savolitinib-induced apoptosis in vitro and significantly promoted tumor regression in BxPC-3 xenograft models, without observable systemic toxicity. Our study reveals a novel resistance mechanism mediated by protective autophagy in response to MET inhibition and provides a rational combinatorial strategy for treating MET-high pancreatic cancer.