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Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1
T-C Teh1,2, N-Y Nguyen1, D M Moujalled1
1Australian Centre for Blood Diseases, Monash University, Alfred Medical Research and Education Precinct, Melbourne, Victoria, Australia.
Abstract:
Targeted therapies are frequently combined with standard cytotoxic drugs to enhance clinical response. Targeting the B-cell lymphoma 2 (BCL-2) family of proteins is an attractive option to combat chemoresistance in leukemia. Preclinical and clinical studies indicate modest single-agent activity with selective BCL-2 inhibitors (for example, venetoclax). We show that venetoclax synergizes with cytarabine and idarubicin to increase antileukemic efficacy in a TP53-dependent manner. Although TP53 deficiency impaired sensitivity to combined venetoclax and chemotherapy, higher-dose idarubicin was able to suppress MCL1 and induce cell death independently of TP53. Consistent with an MCL1-specific effect, cell death from high-dose idarubicin was dependent on pro-apoptotic Bak. Combining higher-dose idarubicin with venetoclax was able to partially overcome resistance in Bak-deficient cells. Using inducible vectors and venetoclax to differentially target anti-apoptotic BCL-2 family members, BCL-2 and MCL1 emerged as critical and complementary proteins regulating cell survival in acute myeloid leukemia. Dual targeting of BCL-2 and MCL1, but not either alone, prolonged survival of leukemia-bearing mice. In conclusion, our findings support the further investigation of venetoclax in combination with standard chemotherapy, including intensified doses of idarubicin. Venetoclax should also be investigated in combination with direct inhibitors of MCL1 as a chemotherapy-free approach in the future.
Insights
Venetoclax combined with chemotherapy enhances leukemia treatment, particularly when targeting BCL-2 and MCL1 proteins. This combination strategy shows promise for improving patient survival in acute myeloid leukemia.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Targeted therapies, including B-cell lymphoma 2 (BCL-2) inhibitors like venetoclax, are explored to overcome chemoresistance in leukemia.
- Selective BCL-2 inhibitors demonstrate modest single-agent activity, necessitating combination strategies for enhanced clinical response.
Purpose of the Study:
- To investigate the synergistic effects of venetoclax with standard chemotherapy agents (cytarabine and idarubicin) in leukemia.
- To elucidate the role of TP53 and BCL-2 family proteins (BCL-2, MCL1) in mediating sensitivity and resistance to these combinations.
Main Methods:
- Preclinical evaluation of venetoclax in combination with cytarabine and idarubicin.
- Assessment of TP53 and MCL1 dependency for cell death induction.
- Utilized inducible vectors to target BCL-2 family members and evaluated outcomes in Bak-deficient models.
Main Results:
- Venetoclax synergized with cytarabine and idarubicin, increasing antileukemic efficacy in a TP53-dependent manner.
- Higher-dose idarubicin suppressed MCL1 and induced TP53-independent cell death, partially overcoming resistance in Bak-deficient cells when combined with venetoclax.
- Dual targeting of BCL-2 and MCL1, but not individual targeting, significantly prolonged survival in leukemia-bearing mice.
Conclusions:
- Findings support the investigation of venetoclax combined with intensified chemotherapy, such as higher-dose idarubicin, for acute myeloid leukemia.
- Exploring venetoclax with direct MCL1 inhibitors presents a potential future chemotherapy-free treatment approach.
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