Concomitant Targeting of FLT3 and BTK Overcomes FLT3 Inhibitor Resistance in Acute Myeloid Leukemia Through the Inhibition of Autophagy

Authors

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

Publication Date

6-1-2023

Journal

Haematologica

DOI

10.3324/haematol.2022.280884

PMID

36226489

PMCID

PMC10230429

PubMedCentral® Posted Date

10-13-2022

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Animals, Mice, Agammaglobulinaemia Tyrosine Kinase, fms-Like Tyrosine Kinase 3, Apoptosis, Cell Line, Tumor, G2 Phase Cell Cycle Checkpoints, Leukemia, Myeloid, Acute, Mutation, Protein Kinase Inhibitors, Autophagy, Tumor Microenvironment

Published Open-Access

yes

Recommended Citation

Zhang, Weiguo; Yu, Guopan; Zhang, Hongying; et al., "Concomitant Targeting of FLT3 and BTK Overcomes FLT3 Inhibitor Resistance in Acute Myeloid Leukemia Through the Inhibition of Autophagy" (2023). Faculty, Staff and Student Publications. 2516.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/2516