ONC213: a novel strategy to resensitize resistant AML cells to venetoclax through induction of mitochondrial stress
Abstract Background Venetoclax + azacitidine is a frontline treatment for older adult acute myeloid leukemia (AML) patients and a salvage therapy for relapsed/refractory patients who have been treated with intensive chemotherapy. While this is an important treatment option, many patients fail to ach...
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| Language: | English |
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BMC
2025-01-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-024-03267-6 |
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| author | Jenna L. Carter Yongwei Su Eman T. Al-Antary Jianlei Zhao Xinan Qiao Guan Wang Holly Edwards Lisa Polin Juiwanna Kushner Sijana H. Dzinic Kathryn White Steven A. Buck Maik Hüttemann Joshua E. Allen Varun V. Prabhu Jay Yang Jeffrey W. Taub Yubin Ge |
| author_facet | Jenna L. Carter Yongwei Su Eman T. Al-Antary Jianlei Zhao Xinan Qiao Guan Wang Holly Edwards Lisa Polin Juiwanna Kushner Sijana H. Dzinic Kathryn White Steven A. Buck Maik Hüttemann Joshua E. Allen Varun V. Prabhu Jay Yang Jeffrey W. Taub Yubin Ge |
| author_sort | Jenna L. Carter |
| collection | DOAJ |
| description | Abstract Background Venetoclax + azacitidine is a frontline treatment for older adult acute myeloid leukemia (AML) patients and a salvage therapy for relapsed/refractory patients who have been treated with intensive chemotherapy. While this is an important treatment option, many patients fail to achieve complete remission and of those that do, majority relapse. Leukemia stem cells (LSCs) are believed to be responsible for AML relapse and can be targeted through oxidative phosphorylation reduction. We previously reported that ONC213 disrupts oxidative phosphorylation and decreases Mcl-1 protein, which play a key role in venetoclax resistance. Here we investigated the antileukemic activity and underlying molecular mechanism of the combination of ONC213 + venetoclax against AML cells. Methods Flow cytometry was used to determine drug-induced apoptosis. Protein level changes were determined by western blot. An AML cell line-derived xenograft mouse model was used to determine the effects of ONC213 + venetoclax on survival. A patient-derived xenograft (PDX) mouse model was used to determine drug effects on CD45+/CD34+/CD38-/CD123 + cells. Colony formation assays were used to assess drug effects on AML progenitor cells. Mcl-1 and Bax/Bak knockdown and Mcl-1 overexpression were used to confirm their role in the mechanism of action. The effect of ONC213 + venetoclax on mitochondrial respiration was determined using a Seahorse bioanalyzer. Results ONC213 + venetoclax synergistically kills AML cells, including those resistant to venetoclax alone as well as venetoclax + azacitidine. The combination significantly reduced colony formation capacity of primary AML progenitors compared to the control and either treatment alone. Further, the combination prolonged survival in an AML cell line-derived xenograft model and significantly decreased LSCs in an AML PDX model. Conclusions ONC213 can resensitize VEN + AZA-resistant AML cells to venetoclax therapy and target LSCs ex vivo and in vivo. |
| format | Article |
| id | doaj-art-56e51a329e5443d8b97c3fa1285a56d4 |
| institution | Kabale University |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-56e51a329e5443d8b97c3fa1285a56d42025-01-12T12:44:42ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-01-0144111710.1186/s13046-024-03267-6ONC213: a novel strategy to resensitize resistant AML cells to venetoclax through induction of mitochondrial stressJenna L. Carter0Yongwei Su1Eman T. Al-Antary2Jianlei Zhao3Xinan Qiao4Guan Wang5Holly Edwards6Lisa Polin7Juiwanna Kushner8Sijana H. Dzinic9Kathryn White10Steven A. Buck11Maik Hüttemann12Joshua E. Allen13Varun V. Prabhu14Jay Yang15Jeffrey W. Taub16Yubin Ge17Cancer Biology Graduate Program, Wayne State University School of MedicineDepartment of Oncology, Wayne State University School of MedicineDivision of Pediatric Hematology/Oncology, Children’s Hospital of MichiganDepartment of Oncology, Wayne State University School of MedicineNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin UniversityNational 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 MedicineDivision of Pediatric Hematology/Oncology, Children’s Hospital of MichiganCancer Biology Graduate Program, Wayne State University School of MedicineChimerix, IncChimerix, IncDepartment of Oncology, Wayne State University School of MedicineMolecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of MedicineCancer Biology Graduate Program, Wayne State University School of MedicineAbstract Background Venetoclax + azacitidine is a frontline treatment for older adult acute myeloid leukemia (AML) patients and a salvage therapy for relapsed/refractory patients who have been treated with intensive chemotherapy. While this is an important treatment option, many patients fail to achieve complete remission and of those that do, majority relapse. Leukemia stem cells (LSCs) are believed to be responsible for AML relapse and can be targeted through oxidative phosphorylation reduction. We previously reported that ONC213 disrupts oxidative phosphorylation and decreases Mcl-1 protein, which play a key role in venetoclax resistance. Here we investigated the antileukemic activity and underlying molecular mechanism of the combination of ONC213 + venetoclax against AML cells. Methods Flow cytometry was used to determine drug-induced apoptosis. Protein level changes were determined by western blot. An AML cell line-derived xenograft mouse model was used to determine the effects of ONC213 + venetoclax on survival. A patient-derived xenograft (PDX) mouse model was used to determine drug effects on CD45+/CD34+/CD38-/CD123 + cells. Colony formation assays were used to assess drug effects on AML progenitor cells. Mcl-1 and Bax/Bak knockdown and Mcl-1 overexpression were used to confirm their role in the mechanism of action. The effect of ONC213 + venetoclax on mitochondrial respiration was determined using a Seahorse bioanalyzer. Results ONC213 + venetoclax synergistically kills AML cells, including those resistant to venetoclax alone as well as venetoclax + azacitidine. The combination significantly reduced colony formation capacity of primary AML progenitors compared to the control and either treatment alone. Further, the combination prolonged survival in an AML cell line-derived xenograft model and significantly decreased LSCs in an AML PDX model. Conclusions ONC213 can resensitize VEN + AZA-resistant AML cells to venetoclax therapy and target LSCs ex vivo and in vivo.https://doi.org/10.1186/s13046-024-03267-6Acute myeloid leukemiaVenetoclaxAzacitidineONC213 |
| spellingShingle | Jenna L. Carter Yongwei Su Eman T. Al-Antary Jianlei Zhao Xinan Qiao Guan Wang Holly Edwards Lisa Polin Juiwanna Kushner Sijana H. Dzinic Kathryn White Steven A. Buck Maik Hüttemann Joshua E. Allen Varun V. Prabhu Jay Yang Jeffrey W. Taub Yubin Ge ONC213: a novel strategy to resensitize resistant AML cells to venetoclax through induction of mitochondrial stress Journal of Experimental & Clinical Cancer Research Acute myeloid leukemia Venetoclax Azacitidine ONC213 |
| title | ONC213: a novel strategy to resensitize resistant AML cells to venetoclax through induction of mitochondrial stress |
| title_full | ONC213: a novel strategy to resensitize resistant AML cells to venetoclax through induction of mitochondrial stress |
| title_fullStr | ONC213: a novel strategy to resensitize resistant AML cells to venetoclax through induction of mitochondrial stress |
| title_full_unstemmed | ONC213: a novel strategy to resensitize resistant AML cells to venetoclax through induction of mitochondrial stress |
| title_short | ONC213: a novel strategy to resensitize resistant AML cells to venetoclax through induction of mitochondrial stress |
| title_sort | onc213 a novel strategy to resensitize resistant aml cells to venetoclax through induction of mitochondrial stress |
| topic | Acute myeloid leukemia Venetoclax Azacitidine ONC213 |
| url | https://doi.org/10.1186/s13046-024-03267-6 |
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