Targeting Compensatory AKT Activation Overcomes Resistance to AXL Inhibition in Acute Lymphoblastic Leukemia

The GAS6/AXL pathway plays a crucial role in promoting tumor survival and therapy resistance in various cancers. However, its significance in acute lymphoblastic leukemia (ALL) and the potential for its therapeutic targeting remain incompletely characterized. We integrated transcriptomic analysis of the public dataset GSE76349 with functional experiments in ALL cell lines. Cabozantinib was evaluated as an AXL inhibitor, and its effects on apoptosis, cell cycle, and signaling pathways were assessed using CCK-8 assays, RNA sequencing, Western blot, and flow cytometry. The functional role of AXL was confirmed via shRNA-mediated knockdown. The synergistic effect of combining cabozantinib with the AKT inhibitor capivasertib was evaluated in vitro and in a murine xenograft model. Bioinformatic analysis identified 8 key genes, including GAS6, associated with chemotherapy resistance. Cabozantinib exhibited strong cytotoxicity in AXL-high ALL cells, inducing apoptosis and G2/M arrest. Compensatory AKT activation was identified as a novel resistance mechanism in MOLT4 cells. AXL knockdown attenuated cabozantinib induced AKT suppression and apoptosis. Combined AXL and AKT inhibition synergistically enhanced anti leukemic effects in vitro and significantly reduced tumor burden in vivo with minimal toxicity. Our findings demonstrate that compensatory AKT activation limits the efficacy of cabozantinib in ALL and establish the combination of cabozantinib and capivasertib as a promising therapeutic strategy for refractory ALL.