Antitumor activity of Gilteritinib, an inhibitor of AXL, in human solid tumor

AXL, a receptor tyrosine kinase, has recently emerged as a potential therapeutic target against various cancer types. Gilteritinib, a FDA-approved small-molecule inhibitor, is used for the treatment of patients with FLT3-mutated acute myeloid leukemia. However, the antitumor activity of Gilteritinib in solid tumors remains poorly elucidated. Here, The antitumor activity of Gilteritinib and molecular mechanisms underlying were explored in the AXL- expressing esophageal cancer (EC), ovarian cancer (OC) and gastric cancer (GC). Our data demonstrated that Gilteritinib significantly inhibited cell proliferation and spheroids formation via triggering apoptosis and cell cycle arrest in AXL-positive EC, OC and GC cells. Moreover, we found that Gilteritinib treatment repressed EC, OC and GC cell migration and invasion. Mechanistically, RNA-seq analysis revealed that Gilteritinib significantly downregulated multiple cancer-related pathways, such as apoptosis, cell cycle, mTOR pathway, AMPK pathway, p53 pathway, FOXO pathway, Hippo pathway and Wnt pathway, etc. Furthermore, Gilteritinib inhibited a unique set of E2F and MYC targets-associated genes in EC, OC and GC cells. Intriguingly, interrogation of the EC, OC and GC cohort demonstrated that these genes were overexpressed and associated with poor prognosis. Finally, Gilteritinib also displayed strong antitumor effects on AXL-positive PDX-derived explants (PDXEs) and PDX-derived organoids (PDXOs) ex vivo, and PDXs in vivo. Collectively, these findings reveals Gilteritinib as a potent therapeutic agent for the treatment of AXL-positive solid tumors.