Hieber, Christoph and Mustafa, Al-Hassan M. and Neuroth, Sarah and Henninger, Sven and Wollscheid, Hans -Peter and Zabkiewicz, Joanna and Lazenby, Michelle and Alvares, Caroline and Mahboobi, Siavosh and Butter, Falk and Brenner, Walburgis and Bros, Matthias and Kraemer, Oliver H. (2024) Inhibitors of the tyrosine kinases FMS-like tyrosine kinase-3 and WEE1 induce apoptosis and DNA damage synergistically in acute myeloid leukemia cells. BIOMEDICINE & PHARMACOTHERAPY, 177: 117076. ISSN 0753-3322, 1950-6007
Full text not available from this repository.Abstract
Hyperactive FMS-like receptor tyrosine kinase-3 mutants with internal tandem duplications (FLT3-ITD) are frequent driver mutations of aggressive acute myeloid leukemia (AML). Inhibitors of FLT3 produce promising results in rationally designed cotreatment schemes. Since FLT3-ITD modulates DNA replication and DNA repair, valid anti-leukemia strategies could rely on a combined inhibition of FLT3-ITD and regulators of cell cycle progression and DNA integrity. These include the WEE1 kinase which controls cell cycle progression, nucleotide synthesis, and DNA replication origin firing. We investigated how pharmacological inhibition of FLT3 and WEE1 affected the survival and genomic integrity of AML cell lines and primary AML cells. We reveal that promising clinical grade and preclinical inhibitors of FLT3 and WEE1 synergistically trigger apoptosis in leukemic cells that express FLT3-ITD. An accumulation of single and double strand DNA damage precedes this process. Mass spectrometry-based proteomic analyses show that FLT3-ITD and WEE1 sustain the expression of the ribonucleotide reductase subunit RRM2, which provides dNTPs for DNA replication. Unlike their strong pro-apoptotic effects on leukemia cells with FLT3-ITD, inhibitors of FLT3 and WEE1 do not damage healthy human blood cells and murine hematopoietic stem cells. Thus, pharmacological inhibition of FLT3-ITD and WEE1 might become an improved, rationally designed therapeutic option.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | REPLICATION; MUTATIONS; HISTONE; FLT3; PHOSPHORYLATION; ADAVOSERTIB; EXPRESSION; CRENOLANIB; INITIATION; AZD1775; AML; DNA replication stress; FLT3-ITD; Inhibitors; Synergism; WEE1 |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 16 Dec 2025 09:39 |
| Last Modified: | 16 Dec 2025 09:39 |
| URI: | https://pred.uni-regensburg.de/id/eprint/65161 |
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