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Updated: Jul 29, 2025
Pre-clinical Evaluation of Tyrosine Kinase Inhibitors for Treatment of Acute Leukemia
Published on: September 18, 2013
AKT inhibition sensitizes acute leukemia cells to S63845-induced apoptosis
Yunjian Li1,2,3, Liang Du1,2,3, Kaiqin Ye2,3
1Basic Medicine College, Anhui Medical University, Hefei, People's Republic of China.
Abstract:
The MCL1 inhibitors are undergoing clinical testing for multiple leukemia. However, because that MCL1 inhibition has on-target hematopoietic, hepatic and cardiac toxicities, there is substantial interest in finding agents can sensitize leukemia cells to the MCL1 inhibitors. Here we describe that the AKT inhibitors MK-2206 and Gsk690693 sensitize multiple leukemia cells to the MCL1 inhibitor S63845. Further experiments demonstrate that MK-2206 and Gsk690693 sensitize S63845 through the mitochondrial apoptosis pathway. Moreover, MK-2206 downregulates the anti-apoptotic protein BCLXL and induces the BH3-only pro-apoptotic protein BAD dephosphorylation and mitochondrial translocation. Knockdown of BAD significantly inhibits MK-2206-induced sensitization to S63845. Thus, our results suggest that MK-2206 sensitizes multiple leukemia cells to S63845-induced apoptosis, with the mechanisms involving BAD dephosphorylation and BCLXL downregulation.
Insights
AKT inhibitors MK-2206 and Gsk690693 enhance leukemia cell sensitivity to MCL1 inhibitors like S63845. This occurs via the mitochondrial apoptosis pathway, involving BAD dephosphorylation and BCLXL downregulation.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- MCL1 inhibitors show promise for leukemia but have toxicities.
- Identifying sensitizing agents is crucial for safer, effective leukemia treatment.
Purpose of the Study:
- To investigate if AKT inhibitors (MK-2206, Gsk690693) can sensitize leukemia cells to MCL1 inhibitor S63845.
- To elucidate the underlying mechanisms of sensitization, focusing on the mitochondrial apoptosis pathway.
Main Methods:
- Treatment of multiple leukemia cell lines with combinations of AKT and MCL1 inhibitors.
- Analysis of apoptosis induction, mitochondrial pathway activation, and protein expression/phosphorylation (BCLXL, BAD).
- Assessment of the role of BAD using knockdown experiments.
Main Results:
- MK-2206 and Gsk690693 significantly sensitized leukemia cells to S63845.
- Sensitization was mediated through the mitochondrial apoptosis pathway.
- MK-2206 downregulated BCLXL and induced BAD dephosphorylation and mitochondrial translocation.
- BAD knockdown abrogated MK-2206-induced sensitization to S63845.
Conclusions:
- AKT inhibitors MK-2206 and Gsk690693 are effective sensitizers for MCL1 inhibitor therapy in leukemia.
- The mechanism involves BAD dephosphorylation and BCLXL downregulation, promoting apoptosis.
- These findings support combining AKT and MCL1 inhibitors for enhanced leukemia treatment.
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