Antitumor activity of gilteritinib, an inhibitor of AXL, in human solid tumors

Abstract

AXL, a receptor tyrosine kinase, has recently emerged as a potential therapeutic target against various types of cancer. 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. In this study, we explored the antitumor activity of gilteritinib in AXL-expressing esophageal cancer (EC), ovarian cancer (OC), and gastric cancer (GC), along with the underlying molecular mechanisms. Our data demonstrated that gilteritinib significantly inhibited cell proliferation and spheroid formation by 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, including those related to apoptosis, the cell cycle, the mTOR pathway, the AMPK pathway, the p53 pathway, the FOXO pathway, the Hippo pathway, and the Wnt pathway. Gilteritinib inhibited a unique set of E2F- and MYC target-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. 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 reveal that gilteritinib represents a potent therapeutic agent for the treatment of AXL-positive solid tumors. (Figure presented.)