Selective Inhibition of HDAC Class I Sensitizes Leukemia and Neuroblastoma Cells to Anticancer Drugs

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Acquired resistance in neuroblastoma (NB) and leukemia poses a significant challenge to current anticancer therapies.
• Targeted therapies like receptor tyrosine kinase (RTK) inhibitors show limited efficacy in patients without specific kinase mutations.
• Histone deacetylase (HDAC) inhibitors have antitumor activity but exhibit substantial whole-body toxicity.

Purpose of the Study:

• To investigate the link between HDAC class I and RTK expression in NB and leukemia.
• To develop a novel HDAC inhibitor with reduced toxicity.
• To explore combination strategies involving HDAC inhibition and RTK inhibition or apoptosis-inducing agents.

Main Methods:

• Transcriptomic data analysis of 701 leukemia and NB patient samples and cell lines.
• Development and toxicity assessment of a novel belinostat derivative, hydrazostat.
• Evaluation of hydrazostat's effect on RTK expression (NTRK1, FGFR3, ROR2, KIT, FLT3).
• Testing combination therapy efficacy with imatinib (RTK inhibitor) and venetoclax (apoptosis inducer).

Main Results:

• HDAC class I expression is linked to RTK expression (KIT, FLT3, AXL, FGFR3, NTRK1) in NB and leukemia.
• Hydrazostat, a novel HDAC inhibitor, targets HDAC class I with limited off-target effects and reduced toxicity compared to other HDAC inhibitors.
• HDAC inhibition by hydrazostat reactivates the expression of key RTKs (NTRK1, FGFR3, ROR2, KIT, FLT3).
• Hydrazostat enhances the efficacy of imatinib and venetoclax in preclinical models.

Conclusions:

• A novel connection between HDACs and RTKs in NB and leukemia resistance is identified.
• Hydrazostat represents a promising therapeutic strategy to overcome resistance to single-agent therapies.
• Combination therapy with hydrazostat and RTK inhibitors or venetoclax offers a potential approach to improve treatment outcomes.