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
Affiliations
Weiguo Zhang
Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas
Guopan Yu
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
Hongying Zhang
Aptose Biosciences, San Diego, California
Mahesh Basyal
Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas
Charlie Ly
Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas
Bin Yuan
Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas
Vivian Ruvolo
Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas
Sujan Piya
Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas
Seemana Bhattacharya
Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas
Qi Zhang
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas
Gautam Borthakur
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
Venkata Battula
Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas
Marina Konopleva
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas
William G. Rice
Aptose Biosciences, San Diego, California
Michael Andreeff
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
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.
