ONC213: a Novel Strategy to Resensitize Resistant AML Cells to Venetoclax Through Induction of Mitochondrial Stress

Overview

Journal J Exp Clin Cancer Res

Publisher Biomed Central

Date 2025 Jan 9

PMID 39780285

Authors

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 Huttemann

Joshua E Allen

Varun V Prabhu

Jay Yang

Jeffrey W Taub

Yubin Ge

Affiliations

Soon will be listed here.

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.

References

Carter J, Hege K, Yang J, Kalpage H, Su Y, Edwards H . Targeting multiple signaling pathways: the new approach to acute myeloid leukemia therapy. Signal Transduct Target Ther. 2020; 5(1):288. PMC: 7746731. DOI: 10.1038/s41392-020-00361-x. View

Luedtke D, Su Y, Ma J, Li X, Buck S, Edwards H . Inhibition of CDK9 by voruciclib synergistically enhances cell death induced by the Bcl-2 selective inhibitor venetoclax in preclinical models of acute myeloid leukemia. Signal Transduct Target Ther. 2020; 5(1):17. PMC: 7042303. DOI: 10.1038/s41392-020-0112-3. View

Sidrauski C, Tsai J, Kampmann M, Hearn B, Vedantham P, Jaishankar P . Pharmacological dimerization and activation of the exchange factor eIF2B antagonizes the integrated stress response. Elife. 2015; 4:e07314. PMC: 4426669. DOI: 10.7554/eLife.07314. View

Li X, Su Y, Hege K, Madlambayan G, Edwards H, Knight T . The HDAC and PI3K dual inhibitor CUDC-907 synergistically enhances the antileukemic activity of venetoclax in preclinical models of acute myeloid leukemia. Haematologica. 2020; 106(5):1262-1277. PMC: 8094102. DOI: 10.3324/haematol.2019.233445. View

Wei A, Montesinos P, Ivanov V, DiNardo C, Novak J, Laribi K . Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020; 135(24):2137-2145. PMC: 7290090. DOI: 10.1182/blood.2020004856. View

Schuler E, Wagner-Drouet E, Ajib S, Bug G, Crysandt M, Dressler S . Treatment of myeloid malignancies relapsing after allogeneic hematopoietic stem cell transplantation with venetoclax and hypomethylating agents-a retrospective multicenter analysis on behalf of the German Cooperative Transplant Study Group. Ann Hematol. 2020; 100(4):959-968. PMC: 8448702. DOI: 10.1007/s00277-020-04321-x. View

Jordan C . Unique molecular and cellular features of acute myelogenous leukemia stem cells. Leukemia. 2002; 16(4):559-62. DOI: 10.1038/sj.leu.2402446. View

Guieze R, Liu V, Rosebrock D, Jourdain A, Hernandez-Sanchez M, Zurita A . Mitochondrial Reprogramming Underlies Resistance to BCL-2 Inhibition in Lymphoid Malignancies. Cancer Cell. 2019; 36(4):369-384.e13. PMC: 6801112. DOI: 10.1016/j.ccell.2019.08.005. View

Stevens B, Jones C, Pollyea D, Culp-Hill R, DAlessandro A, Winters A . Fatty acid metabolism underlies venetoclax resistance in acute myeloid leukemia stem cells. Nat Cancer. 2021; 1(12):1176-1187. PMC: 8054994. DOI: 10.1038/s43018-020-00126-z. View

10.

Chou T . Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 2006; 58(3):621-81. DOI: 10.1124/pr.58.3.10. View

11.

Sidrauski C, McGeachy A, Ingolia N, Walter P . The small molecule ISRIB reverses the effects of eIF2α phosphorylation on translation and stress granule assembly. Elife. 2015; 4. PMC: 4341466. DOI: 10.7554/eLife.05033. View

12.

Carter B, Mak P, Tao W, Warmoes M, Lorenzi P, Mak D . Targeting MCL-1 dysregulates cell metabolism and leukemia-stroma interactions and resensitizes acute myeloid leukemia to BCL-2 inhibition. Haematologica. 2020; 107(1):58-76. PMC: 8719086. DOI: 10.3324/haematol.2020.260331. View

13.

Xie C, Edwards H, Xu X, Zhou H, Buck S, Stout M . Mechanisms of synergistic antileukemic interactions between valproic acid and cytarabine in pediatric acute myeloid leukemia. Clin Cancer Res. 2010; 16(22):5499-510. PMC: 3018695. DOI: 10.1158/1078-0432.CCR-10-1707. View

14.

DiNardo C, Jonas B, Pullarkat V, Thirman M, Garcia J, Wei A . Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. N Engl J Med. 2020; 383(7):617-629. DOI: 10.1056/NEJMoa2012971. View

15.

Lagadinou E, Sach A, Callahan K, Rossi R, Neering S, Minhajuddin M . BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell. 2013; 12(3):329-41. PMC: 3595363. DOI: 10.1016/j.stem.2012.12.013. View

16.

Niu X, Zhao J, Ma J, Xie C, Edwards H, Wang G . Binding of Released Bim to Mcl-1 is a Mechanism of Intrinsic Resistance to ABT-199 which can be Overcome by Combination with Daunorubicin or Cytarabine in AML Cells. Clin Cancer Res. 2016; 22(17):4440-51. PMC: 5010519. DOI: 10.1158/1078-0432.CCR-15-3057. View

17.

Skrtic M, Sriskanthadevan S, Jhas B, Gebbia M, Wang X, Wang Z . Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia. Cancer Cell. 2011; 20(5):674-88. PMC: 3221282. DOI: 10.1016/j.ccr.2011.10.015. View

18.

Bradbury D, Zhu Y, Russell N . Bcl-2 expression in acute myeloblastic leukaemia: relationship with autonomous growth and CD34 antigen expression. Leuk Lymphoma. 1997; 24(3-4):221-8. DOI: 10.3109/10428199709039010. View

19.

Su Y, Carter J, Li X, Fukuda Y, Gray A, Lynch J . The Imipridone ONC213 Targets α-Ketoglutarate Dehydrogenase to Induce Mitochondrial Stress and Suppress Oxidative Phosphorylation in Acute Myeloid Leukemia. Cancer Res. 2024; 84(7):1084-1100. PMC: 11380567. DOI: 10.1158/0008-5472.CAN-23-2659. View

20.

Uphoff C, Drexler H . Detection of mycoplasma contaminations. Methods Mol Biol. 2004; 290:13-23. DOI: 10.1385/1-59259-838-2:013. View