3125 – COMBINING VENETOCLAX TREATMENT WITH AXL KINASE INHIBITION TARGETS CANCER STEM AND PROGENITOR CELLS IN ACUTE MYELOID LEUKEMIA

Abstract

Acute myeloid leukemia (AML) is an aggressive haematological cancer characterized phenotypically by the rapid clonal growth of myeloid cells and an accumulation of immature blasts. Although major progress has been made in identifying different genetic and molecular AML subgroups, treatment and long-term patient outcomes have not changed significantly over the past four decades. Recently, venetoclax (ABT-199), a selective BCL-2 inhibitor, has been approved for the treatment of older patients with AML. However, drug resistance and disease progression on venetoclax as well as the inherent resistance of leukemic stem cells (LSCs) to therapy pose significant clinical challenges. One candidate target for improved therapies is AXL, a member of the TYRO3/AXL/MER (TAM) family of receptor tyrosine kinases that is elevated in AML cells and LSCs, and associated with poor prognosis in AML. To test whether targeting of AXL is a feasible treatment strategy for AML, in particular to eradicate LSCs, we developed a potent and selective AXL inhibitor. We show that AXL inhibition targets AML cells with high AXL expression and synergizes with venetoclax decreasing the viability of primitive AML patient cells and reducing their clonal short- and long-term colony assay outputs compared to single or control treatments. 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. 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 was not toxic to normal BM cells from healthy donors. Hence, our findings identify a promising, improved and specific treatment strategy for AML.