Inhibition of a new AXL isoform, AXL3, induces apoptosis of mantle cell lymphoma cells

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma having a poor overall survival that is in need for the development of new therapeutics. In this study, we report the identification and expression of a new isoform splice variant of the tyrosine kinase receptor AXL in MCL cells. This new AXL isoform, called AXL3, lacks the ligand-binding domain of the commonly described AXL splice variants and is constitutively activated in MCL cells. Interestingly, functional characterization of AXL3, using CRISPR inhibition, revealed that only the knock down of this isoform leads to apoptosis of MCL cells. Importantly, pharmacological inhibition of AXL activity resulted in a significant decrease in the activation of well-known proproliferative and survival pathways activated in MCL cells (ie, beta-catenin, Ak strain transforming, and NF-kappa B). Therapeutically, preclinical studies using a xenograft mouse model of MCL indicated that bemcentinib is more effective than ibrutinib in reducing the tumor burden and to increase the overall survival. Our study highlights the importance of a previously unidentified AXL splice variant in cancer and the potential of bemcentinib as a targeted therapy for MCL.

Automated summary

This study reports the identification and expression of a new AXL splice variant, AXL3, in MCL cells, which is constitutively activated and is essential for MCL cell survival. Inhibition of AXL3 leads to apoptosis of MCL cells and significantly reduces the activation of proproliferative and survival pathways. Bemcentinib shows promise as a targeted therapy for MCL, demonstrating higher efficacy than ibrutinib in reducing tumor burden and increasing overall survival in preclinical studies.