Concomitant targeting of FLT3 and BTK overcomes FLT3 inhibitor resistance in acute myeloid leukemia through the inhibition of autophagy

Weiguo Zhang; Guopan Yu; Hongying Zhang; Mahesh Basyal; Charlie Ly; Bin Yuan; Vivian Ruvolo; Sujan Piya; Seemana Bhattacharya; Qi Zhang; Gautam Borthakur; Venkata Battula; Marina Konopleva; William G Rice; Michael Andreeff

doi:10.3324/haematol.2022.280884

Concomitant targeting of FLT3 and BTK overcomes FLT3 inhibitor resistance in acute myeloid leukemia through the inhibition of autophagy

Haematologica. 2023 Jun 1;108(6):1500-1514. doi: 10.3324/haematol.2022.280884.

Authors

Affiliations

¹ Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
² Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong.
³ Aptose Biosciences, San Diego, California.
⁴ Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
⁵ Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
⁶ Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas. mandreef@mdanderson.org.

Abstract

Strategies to overcome resistance to FMS-like tyrosine kinase 3 (FLT3)-targeted therapy in acute myeloid leukemia (AML) are urgently needed. We identified autophagy as one of the resistance mechanisms, induced by hypoxia and the bone marrow microenvironment via activation of Bruton tyrosine kinase (BTK). Suppressing autophagy/BTK sensitized FLT3- mutated AML to FLT3 inhibitor-induced apoptosis. Furthermore, co-targeting FLT3/BTK/aurora kinases with a novel multikinase inhibitor CG-806 (luxeptinib) induced profound apoptosis in FLT3-mutated AML by co-suppressing FLT3/BTK, antagonizing autophagy, and causing leukemia cell death in FLT3-wildtype AML by aurora kinase-mediated G2/M arrest and polyploidy, in addition to FLT3 inhibition. Thus, CG-806 exerted profound anti-leukemia activity against AML regardless of FLT3 mutation status. CG-806 also significantly reduced AML burden and extended survival in an in vivo patient-derived xenograft leukemia murine model of FLT3 inhibitor-resistant FLT3-ITD/TKD double-mutant primary AML. Taken together, these findings indicate that CG-806 has a unique mechanistic action and pre-clinical activity, which is presently undergoing clinical evaluation in both FLT3 wildtype and mutant AML.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Agammaglobulinaemia Tyrosine Kinase / genetics
Animals
Apoptosis
Autophagy
Cell Line, Tumor
G2 Phase Cell Cycle Checkpoints
Humans
Leukemia, Myeloid, Acute* / drug therapy
Leukemia, Myeloid, Acute* / genetics
Leukemia, Myeloid, Acute* / metabolism
Mice
Mutation
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Tumor Microenvironment
fms-Like Tyrosine Kinase 3* / genetics

Substances

Agammaglobulinaemia Tyrosine Kinase
fms-Like Tyrosine Kinase 3
Protein Kinase Inhibitors
FLT3 protein, human

Grants and funding

P30 CA016672/CA/NCI NIH HHS/United States