Abstract
The acquired resistance of neuroblastoma (NB) and leukemia cells to anticancer therapy remains the major challenge in the treatment of patients with these diseases. Although targeted therapy, such as receptor tyrosine kinase (RTK) inhibitors, has been introduced into clinical practice, its efficacy is limited to patients harboring mutant kinases. Through the analysis of transcriptomic data of 701 leukemia and NB patient samples and cell lines, we revealed that the expression of RTK, such as KIT, FLT3, AXL, FGFR3, and NTRK1, is linked with HDAC class I. Although HDAC inhibitors have antitumor activity, they also have high whole-body toxicity. We developed a novel belinostat derivative named hydrazostat, which targets HDAC class I with limited off-target effects. We compared the toxicity of these drugs within the panel of leukemia and NB cell lines. Next, we revealed that HDAC inhibition with hydrazostat reactivates NTRK1, FGFR3, ROR2, KIT, and FLT3 expression. Based on this finding, we tested the efficacy of hydrazostat in combination with RTK inhibitor imatinib. Additionally, we show the ability of hydrazostat to enhance venetoclax-induced apoptosis. Thus, we reveal the connection between HDACs and RTK and describe a useful strategy to overcome the complications of single-agent therapies.
Highlights
Acute myeloid leukemia (AML) and neuroblastoma (NB) are highly heterogenic malignancies with poor outcomes despite advances in therapeutic regimens and considerable rates of remission
We have shown that the N 0 -propylhydrazide analog of hydroxamic inhibitor belinostat is a potent histone deacetylases (HDACs) class I inhibitor with negligible off-target activities across the other HDACs in human hepatoma cells [33]
We aimed at the investigation of the HDAC class I novel inhibitor hydrazostat’s anticancer effectiveness in leukemia and neuroblastoma cell models, and at the identification of the additional vulnerabilities of cancer cells tightly linked with HDACs
Summary
Acute myeloid leukemia (AML) and neuroblastoma (NB) are highly heterogenic malignancies with poor outcomes despite advances in therapeutic regimens and considerable rates of remission. These types of childhood cancers share common features including the aberrant expression of receptor tyrosine kinases (RTK) such as KIT and NTRK1 [1]. Several RTKs, including the Trk family [4], KIT and PDGFR [5], and ALK [6], have been investigated as potential targets in NB patients; the evidence of their clinical significance was only limited [7,8,9]. RTK targeting has been hampered by acquired resistance across various cancers [10,11,12,13], which clearly illustrates the need for additional therapeutic targets in AML and NB patients
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