دورية أكاديمية
Venetoclax combines synergistically with FLT3 inhibition to effectively target leukemic cells in FLT3-ITD+ acute myeloid leukemia models.
| العنوان: | Venetoclax combines synergistically with FLT3 inhibition to effectively target leukemic cells in FLT3-ITD+ acute myeloid leukemia models. |
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| المؤلفون: | Singh Mali R; Department of Translational Oncology, Genentech, Inc., South San Francisco, CA, USA., Zhang Q; Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA., DeFilippis RA; Division of Hematology and Oncology, University of California at San Francisco, San Francisco, USA., Cavazos A; Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA., Kuruvilla VM; Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA., Raman J; Division of Hematology and Oncology, University of California at San Francisco, San Francisco, USA., Mody V; Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA., Choo EF; Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, CA, USA., Dail M; Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA., Shah NP; Helen Diller Comprehensive Cancer Center, University of California at San Francisco, USA., Konopleva M; Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA., Sampath D; Department of Translational Oncology, Genentech, Inc., South San Francisco, CA, USA., Lasater EA; Department of Translational Oncology, Genentech, Inc., South San Francisco, CA, USA. |
| المصدر: | Haematologica [Haematologica] 2021 Apr 01; Vol. 106 (4), pp. 1034-1046. Date of Electronic Publication: 2021 Apr 01. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Ferrata Storti Foundation Country of Publication: Italy NLM ID: 0417435 Publication Model: Electronic Cited Medium: Internet ISSN: 1592-8721 (Electronic) Linking ISSN: 03906078 NLM ISO Abbreviation: Haematologica Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 1999- : Pavia, Italy : Ferrata Storti Foundation Original Publication: Pavia [etc.] |
| مواضيع طبية MeSH: | Leukemia, Myeloid, Acute*/drug therapy , Leukemia, Myeloid, Acute*/genetics, Adult ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology ; Cell Line, Tumor ; Humans ; Protein Kinase Inhibitors ; Sulfonamides/pharmacology ; Tumor Microenvironment ; fms-Like Tyrosine Kinase 3/genetics |
| مستخلص: | FLT3 internal tandem duplication (FLT3-ITD) mutations account for ~25% of adult acute myeloid leukemia cases and are associated with poor prognosis. Venetoclax, a selective BCL-2 inhibitor, has limited monotherapy activity in relapsed/refractory acute myeloid leukemia with no responses observed in a small subset of FLT3-ITD+ patients. Further, FLT3-ITD mutations emerged at relapse following venetoclax monotherapy and combination therapy suggesting a potential mechanism of resistance. Therefore, we investigated the convergence of FLT3-ITD signaling on the BCL-2 family proteins and determined combination activity of venetoclax and FLT3-ITD inhibition in preclinical models. In vivo, venetoclax combined with quizartinib, a potent FLT3 inhibitor, showed greater anti-tumor efficacy and prolonged survival compared to monotherapies. In a patient-derived FLT3-ITD+ xenograft model, cotreatment with venetoclax and quizartinib at clinically relevant doses had greater anti-tumor activity in the tumor microenvironment compared to quizartinib or venetoclax alone. Use of selective BCL-2 family inhibitors further identified a role for BCL-2, BCL-XL and MCL-1 in mediating survival in FLT3-ITD+ cells in vivo and highlighted the need to target all three proteins for greatest anti-tumor activity. Assessment of these combinations in vitro revealed synergistic combination activity for quizartinib and venetoclax but not for quizartinib combined with BCL-XL or MCL-1 inhibition. FLT3-ITD inhibition was shown to indirectly target both BCL-XL and MCL-1 through modulation of protein expression, thereby priming cells toward BCL-2 dependence for survival. These data demonstrate that FLT3-ITD inhibition combined with venetoclax has impressive anti-tumor activity in FLT3-ITD+ acute myeloid leukemia preclinical models and provides strong mechanistic rational for clinical studies. |
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| المشرفين على المادة: | 0 (Bridged Bicyclo Compounds, Heterocyclic) 0 (Protein Kinase Inhibitors) 0 (Sulfonamides) EC 2.7.10.1 (FLT3 protein, human) EC 2.7.10.1 (fms-Like Tyrosine Kinase 3) N54AIC43PW (venetoclax) |
| تواريخ الأحداث: | Date Created: 20200517 Date Completed: 20210527 Latest Revision: 20210527 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC8017817 |
| DOI: | 10.3324/haematol.2019.244020 |
| PMID: | 32414851 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1592-8721 |
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| DOI: | 10.3324/haematol.2019.244020 |