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2868 Targeting AXL Kinase Sensitizes Acute Myeloid Leukemia Stem and Progenitor Cells to Venetoclax Treatment

Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster III
Hematology Disease Topics & Pathways:
AML, Diseases, Therapies, Combinations, Myeloid Malignancies, Clinically relevant
Monday, December 7, 2020, 7:00 AM-3:30 PM

Katharina Rothe, PhD1,2*, Xiaojia Niu, PhD1,2,3*, Min Chen, PhD2*, Rick Li4*, Sungeun Nam5*, Xiuyan Zhang6*, German Novakovskiy7*, Yehyeon Ahn8,9*, Shenshen Lai4*, Hong Zhang, PhD4*, Jun Yan4*, Hong Liu10*, Yun Zhao, PhD6*, Depei Wu, MD, PhD11, Yubin Ge, PhD12,13,14, Wyeth W. Wasserman9*, Calvin K. Yip15*, Zaihui Zhang, PhD4* and Xiaoyan Jiang, MD, PhD1,16

1Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
2Terry Fox Laboratory, British Columbia Cancer, Vancouver, BC, Canada
3National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering, the Ministry of Education, School of Life Sciences, Jilin University, Changchun, China
4SignalChem Lifesciences Corporation, Richmond, Canada
5Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, CAN
6Cyrus Tang Hematology Center, Soochow University, Suzhou, China
7University of British Columbia, Vancouver, BC, CAN
8Terry Fox Laboratory, British Columbia Cancer, Vancouver, Canada
9Department of Medical Genetics, University of British Columbia, Vancouver, Canada
10Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China
11Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
12Karmanos Cancer Institute Wayne State Univ., Detroit, MI
13Oncology, Wayne State University School of Medicine, Detroit, MI
14Molecular Therapeutics Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI
15Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada
16Terry Fox Laboratory, BC Cancer Research Centre, Vancouver, BC, Canada

Acute myeloid leukemia (AML) is a heterogeneous haematological cancer characterized phenotypically by the rapid clonal growth of myeloid cells and an accumulation of blasts in the peripheral blood and bone marrow of patients. Despite the major progress that has been made in categorizing different genetic and molecular AML subgroups, therapies and long-term patient outcomes have not changed significantly over the past four decades. Recently, venetoclax (ABT-199), a BH3-mimetic and selective BCL-2 inhibitor, was approved for the treatment of older patients with AML. However, the limited efficacy, drug resistance in complex karyotype AML and disease progression on venetoclax as well as the inherent resistance of leukemic stem cells (LSCs) to therapy pose significant clinical challenges, warranting identification of novel targets and improved treatment strategies.

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.

*signifies non-member of ASH