Repurposing cabozantinib with therapeutic potential in KIT-driven t(8;21) acute myeloid leukaemias

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Acute myeloid leukaemia (AML) with t(8;21) often involves aberrant KIT tyrosine kinase activity.
• Cabozantinib is a multi-target tyrosine kinase inhibitor approved for solid tumors, known to inhibit KIT.

Purpose of the Study:

• To evaluate the therapeutic potential of cabozantinib in AML characterized by t(8;21) and KIT mutation.
• To investigate the molecular mechanisms underlying cabozantinib's effect in this AML subtype.

Main Methods:

• In vitro cytotoxicity assays using Kasumi-1 AML cells.
• Analysis of downstream signaling pathways (AKT/mTOR, STAT3, ERK1/2) and cell cycle/apoptosis markers.
• In vivo studies using a mouse xenograft model.
• RNA-sequencing to identify affected pathways.

Main Results:

• Cabozantinib demonstrated significant cytotoxicity (IC50 of 88.06 nM) in Kasumi-1 cells, within achievable plasma levels.
• Treatment suppressed KIT phosphorylation and downstream signaling, altered cell cycle and apoptosis molecules, and disrupted AML1-ETO fusion protein synthesis.
• In vivo, cabozantinib suppressed tumor growth and prolonged survival in mice.
• RNA-sequencing revealed inactivation of mTOR-mediated pathways, downregulation of ribosome biogenesis and glycolysis, and myeloid leukocyte activation.

Conclusions:

• Cabozantinib exhibits promising preclinical efficacy against AML with t(8;21) and KIT mutation.
• The drug's mechanism involves inhibiting KIT signaling, impacting cell cycle and apoptosis, and modulating mTOR pathways.
• Clinical trials are warranted to explore cabozantinib's therapeutic utility in this specific AML patient population.