Abivertinib synergistically strengthens the anti-leukemia activity of venetoclax in acute myeloid leukemia in a BTK-dependent manner.

Molecular Oncology
Shujuan HuangJie Jin

Abstract

B-cell lymphoma 2 (BCL-2), a crucial member of the anti-apoptotic BCL-2 family, is frequently dysregulated in cancer and plays an important role in acute myeloid leukemia (AML). Venetoclax is a highly selective BCL-2 inhibitor that has been approved by the FDA for treating elderly AML patients. However, the emergence of resistance after long-term treatment emphasizes the need for a deeper understanding of the potential mechanisms of resistance and effective rescue methods. By using RNA-seq analysis in two human AML cohorts made up of three patients with complete remission and three patients without remission after venetoclax treatment, we identified that upregulation of BTK enabled AML blast resistance to venetoclax. Interestingly, we found that abivertinib, an oral BTK inhibitor, could synergize with venetoclax to inhibit the proliferation of primary AML cells and cell lines. It is worth noting that the combination of the two effectively enhanced the sensitivity of two AML patients (AML#3 and AML#12) to venetoclax. In this study, we demonstrated that combined use of the two drugs can synergistically inhibit the colony-forming capacity of AML cells, arrest the AML cell cycle in the G0/G1 phase, and inhibit the BCL-2 anti-apopto...Continue Reading

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Citations

Nov 19, 2021·Frontiers of Medicine·Jiansong HuangJie Jin

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Methods Mentioned

BETA
density gradient centrifugation
flow cytometry
transfection
PCR
xenograft

Software Mentioned

image lab [UNK]
graphpad prism

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