Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster III
Hematology Disease Topics & Pathways:
AML, Diseases, Therapies, Combinations, Myeloid Malignancies, Clinically relevant
One candidate target is AXL, a member of the TYRO3/AXL/MER (TAM) family of receptor tyrosine kinases. AXL and its ligand growth arrest–specific gene 6 (GAS6) are elevated in AML patients and LSCs, and associated with poor prognosis. To test whether targeting of the AXL/GAS6 pathway is a feasible treatment strategy for AML, in particular to eradicate LSCs, we developed SLC-391, a novel, potent and selective AXL inhibitor. In vitro and in vivo evaluations of the pharmaceutical properties of SLC-391 indicated reasonable solubility, excellent metabolic stability as well as desirable bioavailability in mice and rats. In silico molecular docking analysis showed that SLC391 can adopt a conformation with surface and charge complementary to the active site of the AXL kinase, potentially engaging in hydrophobic ring-mediated interactions. Further, cell-based studies discovered that SLC-391 targets AML cells with high AXL/GAS6 expression, particularly MLL+ AML cells, and synergizes with venetoclax in cell viability and apoptosis assays (CI<0.6). In addition, simultaneous AXL and BCL-2 inhibition reduced the clonal short- and long-term growth of primitive AML patient cells in CFC re-plating and LTC-IC assays compared to single or control treatments (20-95% inhibition). Moreover, a combination of AXL inhibition and venetoclax treatment was able to target LSCs and AML blasts in two different preclinical patient-derived xenotransplantation (PDX) models, extending the mean survival of these mice by 14-30 days compared to single agents (P<0.025). Mechanistically, single-cell RNA-sequencing and functional validation studies revealed that AXL inhibition perturbs oxidative metabolism, and differentially targets signaling pathways to synergize with venetoclax in leukemic cell killing. Importantly, the combination of AXL inhibition plus venetoclax treatment was not toxic to normal BM cells from healthy donors. Hence, our findings identify a promising, improved and specific treatment strategy for AML, particularly patients with high AXL/GAS6 expression.
Disclosures: No relevant conflicts of interest to declare.
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