A Novel BTK Inhibitor Induces Cells Death and Enhances the Efficacies of Venetoclax in Acute Myeloid Leukemia Cells

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by clonal expansion of immature blast cells in the peripheral blood and bone marrow. AML accounts for nearly 80% of adult leukemia cases. Importantly, receptor tyrosine kinases mutations, as well as high expression of Bruton's tyrosine kinase (BTK) have been identified in AML. BTK is responsible for regulating cell survival and activation through the B-cell receptor signaling pathway, as well as tumor cell adhesion to bone marrow stromal cells. Additionally, anti-apoptotic proteins, especially B-cell lymphoma 2 (BCL-2), are involved in the survival and resistance of AML cells. BCL-2 is overexpressed and is associated with a higher rate of relapse and a decreased sensitivity to chemotherapy. Patients treated with venetoclax, a selective BCL-2 inhibitor, have shown chemotherapeutic resistance in hematologic malignancies, including AML. Drug resistance gradually develops through increasing the expression of BTK and other anti-apoptotic proteins. However, combination therapy can be an effective treatment option for patients to achieve durable chemotherapeutic responses. Multiple combination strategies in the clinic suggest the use of venetoclax with well-established agents in order to increase venetoclax efficacy towards AML and overcome resistance challenges. To identify new therapies for AML, we proposed the use of a novel BTK inhibitor, KS151, alone and in combination with venetoclax to provide an alternative strategy for patients. Interestingly, KS151, a novel BTK inhibitor, induces AML cell death with an average IC₅₀ of 4 μM. Moreover, KS151 was able to increase the efficacy of venetoclax towards AML cells. In our panel of three AML cell lines: Kusami-1, U937, and THP-1, our western blot showed Kusami-1 had the highest expression of BTK and BCL-2 proteins. Remarkably, in a dose-dependent manner, KS151 induces Kusami-1 cell death by targeting BTK and enhances the downregulation of BCL-2 in combination with venetoclax. Annexin V staining in flow cytometry also demonstrated KS151 in combination therapy with venetoclax resulted in apoptosis in nearly 95% of AML cells. Taken together, our findings propose KS151 alone or in combination with venetoclax as a promising potential AML killer and may represent a new viable treatment. Future studies will uncover the mechanism of action of KS151 and include the assessment in patient samples and in vivo studies.

No relevant conflicts of interest to declare.