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

Kuan-Wei Su,Hsin-An Hou,Liang-In Lin,Da-Liang Ou,Yu-Hsuan Fu,Hwei-Fang Tien

doi:10.1038/s41417-021-00329-1

Kuan-Wei Su, Hsin-An Hou + Show 4 more

Open Access

https://doi.org/10.1038/s41417-021-00329-1

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Abstract

Cabozantinib is an orally available, multi-target tyrosine kinase inhibitor approved for the treatment of several solid tumours and known to inhibit KIT tyrosine kinase. In acute myeloid leukaemia (AML), aberrant KIT tyrosine kinase often coexists with t(8;21) to drive leukaemogenesis. Here we evaluated the potential therapeutic effect of cabozantinib on a selected AML subtype characterised by t(8;21) coupled with KIT mutation. Cabozantinib exerted substantial cytotoxicity in Kasumi-1 cells with an IC50 of 88.06 ± 4.32 nM, which was well within clinically achievable plasma levels. The suppression of KIT phosphorylation and its downstream signals, including AKT/mTOR, STAT3, and ERK1/2, was elicited by cabozantinib treatment and associated with subsequent alterations of cell cycle- and apoptosis-related molecules. Cabozantinib also disrupted the synthesis of an AML1-ETO fusion protein in a dose- and time-dependent manner. In a mouse xenograft model, cabozantinib suppressed tumourigenesis at 10 mg/kg and significantly prolonged survival of the mice. Further RNA-sequencing analysis revealed that mTOR-mediated signalling pathways were substantially inactivated by cabozantinib treatment, causing the downregulation of ribosome biogenesis and glycolysis, along with myeloid leukocyte activation. We suggest that cabozantinib may be effective in the treatment of AML with t(8;21) and KIT mutation. Relevant clinical trials are warranted.

Highlights

Differentiation arrest and uncontrollable proliferation of myeloid progenitor cells induce acute myeloid leukaemia (AML), a genetically heterogeneous clonal malignancy [1]
We found that treatment of Kasumi-1 cells with 50 nM cabozantinib induced significant G0/G1 cell-cycle arrest within 24 h in a dose-dependent manner (Fig. 1B)
Cabozantinib downregulated the G1/S transition regulator cyclin E and upregulated the cyclin-dependent kinase (CDK) inhibitor p27 (Fig. 1C), which led to G0/G1 cell-cycle arrest, suggesting that their dysregulation contributed to the inhibitory effects

Summary

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Differentiation arrest and uncontrollable proliferation of myeloid progenitor cells induce acute myeloid leukaemia (AML), a genetically heterogeneous clonal malignancy [1]. AML1-ETO alone fails to induce leukaemogenesis; an additional coinciding mutation such as KIT, FLT3, JAK2, RAS, and PDGFR, is needed for full-blown leukaemia [5]. (GDSC, https://www.cancerrxgene.org/), to assess the activity of cabozantinib against haematological malignancies. Among these malignancies, cabozantinib was especially effective against AML, according to low IC50 values (Supplementary Fig. 1A–C). Our previous sensitivity assessment of leukaemic cell lines (MV4-11, MOLM13, OCI-AML3, THP-1, RS4;11, K562, U937, and HL60) indicated that nanomolar cabozantinib was selectively cytotoxic in leukaemic cells with FLT3-ITD [12]. Based on the pharmacological potential of cabozantinib, we investigated the anti-leukaemia effect of cabozantinib on another subtype AML harbouring both KIT mutation and t (8;21)

Materials and methods

Results

Discussion

Compliance with ethical standards