Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1
| العنوان: | Enhancing venetoclax activity in acute myeloid leukemia by co-targeting MCL1 |
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| المؤلفون: | Stefan P Glaser, Mark A. Guthridge, K. Cummins, Nhu Y.N. Nguyen, Piers Blombery, David C.S. Huang, Kurt Lackovic, Paul G Ekert, Sewa Rijal, Andrew W. Roberts, Guillaume Lessene, Andrew H. Wei, David J. Segal, Ella R. Thompson, Giovanna Pomilio, Donia M Moujalled, Tse-Chieh Teh, Anissa Jabbour |
| المصدر: | Leukemia. 32:303-312 |
| بيانات النشر: | Springer Science and Business Media LLC, 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Myeloid, Cell Survival, medicine.medical_treatment, Apoptosis, Biology, Pharmacology, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Mice, Inbred NOD, Cell Line, Tumor, Antineoplastic Combined Chemotherapy Protocols, medicine, Animals, Humans, Idarubicin, MCL1, Sulfonamides, Chemotherapy, Venetoclax, Myeloid leukemia, Hematology, Bridged Bicyclo Compounds, Heterocyclic, medicine.disease, Leukemia, Myeloid, Acute, Leukemia, 030104 developmental biology, medicine.anatomical_structure, Proto-Oncogene Proteins c-bcl-2, Oncology, chemistry, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Cancer research, Cytarabine, Myeloid Cell Leukemia Sequence 1 Protein, medicine.drug |
| الوصف: | 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. |
| تدمد: | 1476-5551 0887-6924 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7d8b647cb968670d332b8fc4be880c93Test https://doi.org/10.1038/leu.2017.243Test |
| حقوق: | CLOSED |
| رقم الانضمام: | edsair.doi.dedup.....7d8b647cb968670d332b8fc4be880c93 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14765551 08876924 |
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