Academic Journal
Comprehensive genomic characterization of gene therapy-induced T-cell acute lymphoblastic leukemia
| العنوان: | Comprehensive genomic characterization of gene therapy-induced T-cell acute lymphoblastic leukemia |
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| المؤلفون: | Horak, Peter, Uhrig, Sebastian, Witzel, Maximilian, Gil-Farina, Irene, Hutter, Barbara, Rath, Tim, Gieldon, Laura, Balasubramanian, Gnana Prakash, Pastor, Xavier, Heilig, Christoph E., Richter, Daniela, Schröck, Evelin, Ball, Claudia R., Brors, Benedikt, Braun, Christian Joerg, Albert, Michael H., Scholl, Claudia, von Kalle, Christof, Schmidt, Manfred, Fröhling, Stefan, Klein, Christoph, Glimm, Hanno |
| المصدر: | http://lobid.org/resources/99370672770606441#!, 34(10):2785-2789. |
| سنة النشر: | 2020 |
| المجموعة: | Publisso (ZB MED-Publikationsportal Lebenswissenschaften) |
| مصطلحات موضوعية: | Letter, Polymorphism, Single Nucleotide [MeSH], Humans [MeSH], Genetic Therapy/adverse effects [MeSH], Neoplasms, Second Primary/diagnosis [MeSH], Whole Exome Sequencing [MeSH], Genomics/methods [MeSH], Translational research, Genetic Testing [MeSH], Wiskott-Aldrich Syndrome/complications [MeSH], Wiskott-Aldrich Syndrome/therapy [MeSH], Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis [MeSH], Immunophenotyping [MeSH], Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/etiology [MeSH], Genetic Therapy/methods [MeSH], Wiskott-Aldrich Syndrome/genetics [MeSH], Biomarkers, Tumor [MeSH], Gene Expression Profiling [MeSH], Second Primary/etiology [MeSH], Cancer genomics |
| الوصف: | Drug combinations that target critical pathways are a mainstay of cancer care. To improve current approaches to combination treatment of chronic lymphocytic leukemia (CLL) and gain insights into the underlying biology, we studied the effect of 352 drug combination pairs in multiple concentrations by analysing ex vivo drug response of 52 primary CLL samples, which were characterized by 'omics' profiling. Known synergistic interactions were confirmed for B-cell receptor (BCR) inhibitors with Bcl-2 inhibitors and with chemotherapeutic drugs, suggesting that this approach can identify clinically useful combinations. Moreover, we uncovered synergistic interactions between BCR inhibitors and afatinib, which we attribute to BCR activation by afatinib through BLK upstream of BTK and PI3K. Combinations of multiple inhibitors of BCR components (e.g., BTK, PI3K, SYK) had effects similar to the single agents. While PI3K and BTK inhibitors produced overall similar effects in combinations with other drugs, we uncovered a larger response heterogeneity of combinations including PI3K inhibitors, predominantly in CLL with mutated IGHV, which we attribute to the target's position within the BCR-signaling pathway. Taken together, our study shows that drug combination effects can be effectively queried in primary cancer cells, which could aid discovery, triage and clinical development of drug combinations. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | https://repository.publisso.de/resource/frl:6471046; https://doi.org/10.1038/s41375-020-0779-z; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321895/ |
| DOI: | 10.1038/s41375-020-0779-z |
| الاتاحة: | https://repository.publisso.de/resource/frl:6471046 https://doi.org/10.1038/s41375-020-0779-z https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8321895/ |
| Rights: | https://creativecommons.org/licenses/by/4.0/ |
| رقم الانضمام: | edsbas.3C523EA5 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41375-020-0779-z |
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