A dual MET/AXL small‐molecule inhibitor exerts efficacy against gastric carcinoma through killing cancer cells as well as modulating tumor microenvironment

Abstract

The receptor tyrosine kinases MET and AXL have been implicated in tumorigenesis and aggressiveness of multiple malignancies. We performed this study to evaluate the antitumor impact of LY2801653, a dual MET and AXL inhibitor on gastric cancer and to elucidate the underlying mechanisms. In the present study, tissue microarrays containing gastric cancer tissues were stained with MET and AXL antibodies, which showed the prognostic values of MET and AXL. Administration of LY2801653 inhibited cell proliferation, migration, epithelial‐mesenchymal transition, induced apoptosis, and cell cycle arrest. Xenograft mouse models showed suppressed cell proliferation of tumors in high MET and AXL expression cells. LY2801653 also inhibited the growth of MET and AXL‐independent cells at higher but clinically relevant doses through decreased angiogenesis and M2 macrophages in the tumor microenvironment. In conclusion, our study provides evidence for MET and AXL as prognostic biomarkers and potential therapeutic targets in gastric cancer. The dual MET/AXL inhibitor LY2801653 represents a promising therapeutic strategy for the treatment of patients with gastric carcinoma.

ENKUR recruits FBXW7 to ubiquitinate and degrade MYH9 and further suppress MYH9‐induced deubiquitination of β‐catenin to block gastric cancer metastasis

“…2 The higher metastasis property makes GC cells easily have direct infiltration, hematogenous metastasis, peritoneal implantation, and lymphatic metastasis, which limits the application and effect of surgical therapy. Despite advances in chemical therapy, targeted therapy, and immune therapy in recent years, [3][4][5] the prognosis of patients with GC remains poor because of cancer metastasis. 6 ENKUR is highly expressed in the testis and vomeronasal organ and is identified as a transient receptor potential-canonical (TRPC) channel binding protein.…”

Discovery of 10H-Benzo[b]pyrido[2,3-e][1,4]oxazine AXL Inhibitors via Structure-Based Drug Design Targeting c-Met Kinase

“…The vitamin K-dependent protein growth arrest-specific protein 6 (Gas6) is a soluble glycoprotein that serves as a common ligand of TAM receptors and binds AXL in the highest affinity. , And the Gas6-stimulated AXL activation mediates cell survival, proliferation, migration, angiogenesis, and inflammatory immune response. , Abnormal stimulation of AXL causes epithelial–mesenchymal transition (EMT) process and promotes the invasive and metastatic profiles of cancer cells. Moreover, aberrant AXL activation could generate drug resistance to chemotherapy, targeted therapies, as well as immunotherapy. ,, Inhibiting the aberrant AXL signaling with therapeutic agents (small-molecule inhibitors or antibodies) or genetic tools (RNAi or shRNA) has proven preferable antitumor efficacies in both preclinical and clinical studies, which highlights AXL as an attractive drug target for cancer therapy. , …”

“…9,10,12 Inhibiting the aberrant AXL signaling with therapeutic agents (small-molecule inhibitors or antibodies) or genetic tools (RNAi or shRNA) has proven preferable antitumor efficacies in both preclinical and clinical studies, which highlights AXL as an attractive drug target for cancer therapy. 13,14 Development of the small-molecule AXL inhibitors has achieved significant progress with several inhibitors in clinical studies. 13 Small-molecular AXL inhibitors are categorized into two types according to the inhibitor-kinase binding modes.…”