Targeting Axl/Mer with ONO-9330547: Overcoming Drug Resistance in Acute Myeloid Leukemia

In a study involving female SCID mice with implanted AML cell lines, the orally administered compound ONO-9330547 was evaluated for its effects on tumor growth. The treatment was initiated when the average tumor size reached 100-200 mm3 and continued for 24 days at varying doses. Tumor sizes were monitored bi-weekly, and animals were sacrificed once tumors reached a maximum volume of 2,000 mm3.
The compound showed significant inhibition of phosphorylated Axl and Mer proteins, leading to tumor growth suppression and apoptosis induction. In the MV-4-11 xenograft model, tumor growth inhibition was substantial, with a 40% reduction in the 0.3 mg/kg twice daily group, 78% in the 1 mg/kg group, and complete remission in the 3 mg/kg group. Notably, sustained P-Axl inhibition was observed with higher doses, and a combination of ONO-9330547 with Ara-C showed enhanced anti-tumor effects compared to individual treatments.
Post-chemotherapy up-regulation of Axl and Mer was also noted, suggesting a potential for combining ONO-9330547 with standard therapies to combat resistance in AML. The study concludes that ONO-9330547 is a potent dual inhibitor of Axl and Mer, demonstrating efficacy against AML cells and the potential to be combined with existing treatments. Further research is being conducted to explore the role of Axl and Mer in different types of leukemia.