Intact TP-53 function is essential for sustaining durable responses to BH3-mimetic drugs in leukemias
| العنوان: | Intact TP-53 function is essential for sustaining durable responses to BH3-mimetic drugs in leukemias |
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| المؤلفون: | Rachel Thijssen, Edward Chew, Sarah S. Gabriel, Brandon J. Aubrey, Ashish Bajel, Andrew W. Roberts, Andreas Strasser, Marie Schoumacher, David A. Stroud, Chris D. Riffkin, Claudia Bruedigam, Donia M Moujalled, Natasha S Anstee, Tirta Mario Djajawi, Veronique Litalien, Ruth M. Kluck, Lin Tai, Andrew H. Wei, Thomas David Morley, Zhen Xu, Giovanna Pomilio, Sarah T. Diepstraten, Sarah MacRaild, Axel Kallies, Christoffer Flensburg, Boris Reljic, Steven W. Lane, Maoshan Chen, Catherine Chang, Gemma L. Kelly, David C. S. Huang, Fiona C. Brown, Sébastien Banquet, Michael A. Dengler, Melissa X Shi, Ian J. Majewski |
| المصدر: | Blood. 137:2721-2735 |
| بيانات النشر: | American Society of Hematology, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Myeloid, Chronic lymphocytic leukemia, Apoptosis, Mice, SCID, Biochemistry, Oxidative Phosphorylation, Mice, chemistry.chemical_compound, 0302 clinical medicine, Mice, Inbred NOD, Mice, Knockout, Sulfonamides, Hematology, Indolizines, Myeloid leukemia, Neoplasm Proteins, Leukemia, Myeloid, Acute, Leukemia, medicine.anatomical_structure, Proto-Oncogene Proteins c-bcl-2, 030220 oncology & carcinogenesis, medicine.drug, medicine.medical_specialty, Programmed cell death, Morpholines, Immunology, Azacitidine, Antineoplastic Agents, 03 medical and health sciences, Cell Line, Tumor, Proto-Oncogene Proteins, Internal medicine, medicine, Animals, Humans, business.industry, Venetoclax, Interleukin-2 Receptor alpha Subunit, Cell Biology, Bridged Bicyclo Compounds, Heterocyclic, Genes, p53, Isoquinolines, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, Xenograft Model Antitumor Assays, Peptide Fragments, 030104 developmental biology, chemistry, Cancer research, Myeloid Cell Leukemia Sequence 1 Protein, CRISPR-Cas Systems, Tumor Suppressor Protein p53, Apoptosis Regulatory Proteins, business, DNA Damage |
| الوصف: | Selective targeting of BCL-2 with the BH3-mimetic venetoclax has been a transformative treatment for patients with various leukemias. TP-53 controls apoptosis upstream of where BCL-2 and its prosurvival relatives, such as MCL-1, act. Therefore, targeting these prosurvival proteins could trigger apoptosis across diverse blood cancers, irrespective of TP53 mutation status. Indeed, targeting BCL-2 has produced clinically relevant responses in blood cancers with aberrant TP-53. However, in our study, TP53-mutated or -deficient myeloid and lymphoid leukemias outcompeted isogenic controls with intact TP-53, unless sufficient concentrations of BH3-mimetics targeting BCL-2 or MCL-1 were applied. Strikingly, tumor cells with TP-53 dysfunction escaped and thrived over time if inhibition of BCL-2 or MCL-1 was sublethal, in part because of an increased threshold for BAX/BAK activation in these cells. Our study revealed the key role of TP-53 in shaping long-term responses to BH3-mimetic drugs and reconciled the disparate pattern of initial clinical response to venetoclax, followed by subsequent treatment failure among patients with TP53-mutant chronic lymphocytic leukemia or acute myeloid leukemia. In contrast to BH3-mimetics targeting just BCL-2 or MCL-1 at doses that are individually sublethal, a combined BH3-mimetic approach targeting both prosurvival proteins enhanced lethality and durably suppressed the leukemia burden, regardless of TP53 mutation status. Our findings highlight the importance of using sufficiently lethal treatment strategies to maximize outcomes of patients with TP53-mutant disease. In addition, our findings caution against use of sublethal BH3-mimetic drug regimens that may enhance the risk of disease progression driven by emergent TP53-mutant clones. |
| تدمد: | 1528-0020 0006-4971 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f7eddd95d812425ed1bd085adc1b7dd3Test https://doi.org/10.1182/blood.2020010167Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....f7eddd95d812425ed1bd085adc1b7dd3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15280020 00064971 |
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