Dual SYK/JAK inhibition overcomes ibrutinib resistance in chronic lymphocytic leukemia: Cerdulatinib, but not ibrutinib, induces apoptosis of tumor cells protected by the microenvironment

Ibrutinib, a BTK inhibitor, has shown impressive efficacy in treating chronic lymphocytic leukemia (CLL), but it largely fails to directly induce cell death or eliminate CLL malignant clones. This limitation has led to the development of resistance, with resistant patients experiencing a median survival of only 3-4 months. To address this challenge, novel therapeutic approaches are necessary to prevent resistance, enhance treatment outcomes, and ultimately cure the disease.

In this context, we investigated the potential of cerdulatinib, a novel agent that targets both the BCR and JAK-STAT pathways. Cerdulatinib selectively inhibits SYK (a BCR component) and JAK kinases, offering a dual-targeting approach. Our studies revealed that cerdulatinib effectively inhibited tumor growth in 60 primary CLL patient samples, particularly in those with poor prognostic features. Unlike ibrutinib, cerdulatinib overcomes the supportive effects of the microenvironment and induces cell death in CLL cells at clinically achievable concentrations. Additionally, cerdulatinib was effective against ibrutinib-resistant primary CLL cells and lymphoma cells with the BTKC481S mutation. The observed anti-tumor effects correlated with inhibition of BCR and JAK-STAT signaling pathways, as well as downstream suppression of AKT, ERK, and NFκB functions. Overall, our findings suggest that dual targeting of the BCR and JAK-STAT pathways is a more effective strategy compared to single BTK inhibition.