The combination of CUDC-907 and gilteritinib shows promising in vitro and in vivo antileukemic activity against FLT3-ITD AML
Abstract About 25% of patients with acute myeloid leukemia (AML) harbor FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations and their prognosis remains poor. Gilteritinib is a FLT3 inhibitor approved by the US FDA for use in adult FLT3-mutated relapsed or refractory AML pat...
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doaj-70d217bd11434be4bbb6948db97bb9fd2021-06-13T11:14:41ZengNature Publishing GroupBlood Cancer Journal2044-53852021-06-0111611710.1038/s41408-021-00502-7The combination of CUDC-907 and gilteritinib shows promising in vitro and in vivo antileukemic activity against FLT3-ITD AMLXinan Qiao0Jun Ma1Tristan Knight2Yongwei Su3Holly Edwards4Lisa Polin5Jing Li6Juiwanna Kushner7Sijana H. Dzinic8Kathryn White9Jian Wang10Hai Lin11Yue Wang12Liping Wang13Guan Wang14Jeffrey W. Taub15Yubin Ge16National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin UniversityNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin UniversityDepartment of Pediatrics, Wayne State University School of MedicineNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin UniversityDepartment of Oncology, Wayne State University School of MedicineDepartment of Oncology, Wayne State University School of MedicineDepartment of Oncology, Wayne State University School of MedicineDepartment of Oncology, Wayne State University School of MedicineDepartment of Oncology, Wayne State University School of MedicineDepartment of Oncology, Wayne State University School of MedicineDepartment of Pathology, Wayne State University School of MedicineDepartment of Hematology and Oncology, The First Hospital of Jilin UniversityDepartment of Pediatric Hematology and Oncology, The First Hospital of Jilin UniversityNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin UniversityNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin UniversityDepartment of Pediatrics, Wayne State University School of MedicineDepartment of Oncology, Wayne State University School of MedicineAbstract About 25% of patients with acute myeloid leukemia (AML) harbor FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations and their prognosis remains poor. Gilteritinib is a FLT3 inhibitor approved by the US FDA for use in adult FLT3-mutated relapsed or refractory AML patients. Monotherapy, while efficacious, shows short-lived responses, highlighting the need for combination therapies. Here we show that gilteritinib and CUDC-907, a dual inhibitor of PI3K and histone deacetylases, synergistically induce apoptosis in FLT3-ITD AML cell lines and primary patient samples and have striking in vivo efficacy. Upregulation of FLT3 and activation of ERK are mechanisms of resistance to gilteritinib, while activation of JAK2/STAT5 is a mechanism of resistance to CUDC-907. Gilteritinib and CUDC-907 reciprocally overcome these mechanisms of resistance. In addition, the combined treatment results in cooperative downregulation of cellular metabolites and persisting antileukemic effects. CUDC-907 plus gilteritinib shows synergistic antileukemic activity against FLT3-ITD AML in vitro and in vivo, demonstrating strong translational therapeutic potential.https://doi.org/10.1038/s41408-021-00502-7 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xinan Qiao Jun Ma Tristan Knight Yongwei Su Holly Edwards Lisa Polin Jing Li Juiwanna Kushner Sijana H. Dzinic Kathryn White Jian Wang Hai Lin Yue Wang Liping Wang Guan Wang Jeffrey W. Taub Yubin Ge |
spellingShingle |
Xinan Qiao Jun Ma Tristan Knight Yongwei Su Holly Edwards Lisa Polin Jing Li Juiwanna Kushner Sijana H. Dzinic Kathryn White Jian Wang Hai Lin Yue Wang Liping Wang Guan Wang Jeffrey W. Taub Yubin Ge The combination of CUDC-907 and gilteritinib shows promising in vitro and in vivo antileukemic activity against FLT3-ITD AML Blood Cancer Journal |
author_facet |
Xinan Qiao Jun Ma Tristan Knight Yongwei Su Holly Edwards Lisa Polin Jing Li Juiwanna Kushner Sijana H. Dzinic Kathryn White Jian Wang Hai Lin Yue Wang Liping Wang Guan Wang Jeffrey W. Taub Yubin Ge |
author_sort |
Xinan Qiao |
title |
The combination of CUDC-907 and gilteritinib shows promising in vitro and in vivo antileukemic activity against FLT3-ITD AML |
title_short |
The combination of CUDC-907 and gilteritinib shows promising in vitro and in vivo antileukemic activity against FLT3-ITD AML |
title_full |
The combination of CUDC-907 and gilteritinib shows promising in vitro and in vivo antileukemic activity against FLT3-ITD AML |
title_fullStr |
The combination of CUDC-907 and gilteritinib shows promising in vitro and in vivo antileukemic activity against FLT3-ITD AML |
title_full_unstemmed |
The combination of CUDC-907 and gilteritinib shows promising in vitro and in vivo antileukemic activity against FLT3-ITD AML |
title_sort |
combination of cudc-907 and gilteritinib shows promising in vitro and in vivo antileukemic activity against flt3-itd aml |
publisher |
Nature Publishing Group |
series |
Blood Cancer Journal |
issn |
2044-5385 |
publishDate |
2021-06-01 |
description |
Abstract About 25% of patients with acute myeloid leukemia (AML) harbor FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations and their prognosis remains poor. Gilteritinib is a FLT3 inhibitor approved by the US FDA for use in adult FLT3-mutated relapsed or refractory AML patients. Monotherapy, while efficacious, shows short-lived responses, highlighting the need for combination therapies. Here we show that gilteritinib and CUDC-907, a dual inhibitor of PI3K and histone deacetylases, synergistically induce apoptosis in FLT3-ITD AML cell lines and primary patient samples and have striking in vivo efficacy. Upregulation of FLT3 and activation of ERK are mechanisms of resistance to gilteritinib, while activation of JAK2/STAT5 is a mechanism of resistance to CUDC-907. Gilteritinib and CUDC-907 reciprocally overcome these mechanisms of resistance. In addition, the combined treatment results in cooperative downregulation of cellular metabolites and persisting antileukemic effects. CUDC-907 plus gilteritinib shows synergistic antileukemic activity against FLT3-ITD AML in vitro and in vivo, demonstrating strong translational therapeutic potential. |
url |
https://doi.org/10.1038/s41408-021-00502-7 |
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