FLT3 inhibition by olverembatinib (HQP1351) downregulates MCL-1 and synergizes with BCL-2 inhibitor lisaftoclax (APG-2575) in preclinical models of FLT3-ITD mutant acute myeloid leukemia

Fang, Douglas D.; Zhu, Hengrui; Tang, Qiuqiong; Wang, Guangfeng; Min, Ping; Wang, Qixin; Li, Na; Yang, Dajun; Zhai, Yifan

doi:10.1016/j.tranon.2021.101244

Cited by 18 publications

(15 citation statements)

References 45 publications

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“…In these AML cells, the increased cleavage of caspase 3 and poly(ADP-ribose) polymerase (PARP) prove the enhanced apoptosis. This finding also indirectly proves that expansion of FLT3-ITD is indeed involved in the resistance of cells to venetoclax [ 67 ].…”

Section: Introductionmentioning

confidence: 67%

Progress in understanding the mechanisms of resistance to BCL-2 inhibitors

2022

Exp Hematol Oncol

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Venetoclax is a new type of BH3 mimetic compound that can target the binding site in the BCL-2 protein and induce apoptosis in cancer cells by stimulating the mitochondrial apoptotic pathway. Venetoclax is especially used to treat haematological malignancies. However, with the recent expansion in the applications of venetoclax, some cases of venetoclax resistance have appeared, posing a major problem in clinical treatment. In this article, we explored several common mechanisms of venetoclax resistance. Increased expression of the antiapoptotic proteins MCL-1 and BCL-XL plays a key role in conferring cellular resistance to venetoclax. These proteins can bind to the released BIM in the context of venetoclax binding to BCL-2 and thus continue to inhibit mitochondrial apoptosis. Structural mutations in BCL-2 family proteins caused by genetic instability lead to decreased affinity for venetoclax and inhibit the intrinsic apoptosis pathway. Mutation or deletion of the BAX gene renders the BAX protein unable to anchor to the outer mitochondrial membrane to form pores. In addition to changes in BCL-2 family genes, mutations in other oncogenes can also confer resistance to apoptosis induced by venetoclax. TP53 mutations and the expansion of FLT3-ITD promote the expression of antiapoptotic proteins MCL-1 and BCL-XL through multiple signalling pathways, and interfere with venetoclax-mediated apoptosis processes depending on their affinity for BH3-only proteins. Finally, the level of mitochondrial oxidative phosphorylation in venetoclax-resistant leukaemia stem cells is highly abnormal. Not only the metabolic pathways but also the levels of important metabolic components are changed, and all of these alterations antagonize the venetoclax-mediated inhibition of energy metabolism and promote the survival and proliferation of leukaemia stem cells. In addition, venetoclax can change mitochondrial morphology independent of the BCL-2 protein family, leading to mitochondrial dysfunction. However, mitochondria resistant to venetoclax antagonize this effect, forming tighter mitochondrial cristae, which provide more energy for cell survival.

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Section: Introductionmentioning

confidence: 67%

Progress in understanding the mechanisms of resistance to BCL-2 inhibitors

2022

Exp Hematol Oncol

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“…According to previous test methods [ 26 ], to detect early and late apoptosis, using Annexin V-FITC/PI dual staining detection kits (Beyotime, Shanghai, China). Cells(1 × 10 6 ) were stained with 5 µL of Annexin V and 10 µL of PI in 198 μL of 1× binding buffer for 15 min at room temperature in the dark.…”

Section: Methodsmentioning

confidence: 99%

Shikonin induces apoptosis and autophagy via downregulation of pyrroline-5-carboxylate reductase1 in hepatocellular carcinoma cells

et al. 2022

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Shikonin(SK) is a natural small molecule naphthoquinone compound, which has anti-cancer activity in various human malignant tumors. Pyrroline-5-carboxylate reductase 1(PYCR1) is involved in tumorigenesis and regulates various cellular processes, including growth, invasion, migration, and apoptosis. However, the effect of SK and PYCR1 on apoptosis and autophagy in hepatocellular carcinoma are unclear. Our goal is to determine the internal molecular mechanism of the interaction between SK and PYCR1 and its role in the occurrence and development of liver cancer. The CCK8 assay, wound healing assay, and transwell assays show that SK and siPYCR1(gene silence PYCR1) inhibited the malignant phenotype of HCC cells, including cell viability, colony formation, migration, and invasion, respectively. The flow cytometry assays and immunofluorescence show that SK and siPYCR1 activated apoptosis and autophagy, respectively. SK induces apoptosis and autophagy in a dose-dependent manner. In addition, HCC cells were transfected with small interference fragment PYCR1 siRNA to construct siPYCR1 and SK single treatment group and co-treatment group to verify the interaction between SK and PYCR1. The Western blot identified that PI3K/Akt/mTOR signal pathway protein expression was significantly downregulated in HCC cells treated with SK and siPYCR1 together. Collectively, SK may induce apoptosis and autophagy by reducing the expression of PYCR1 and suppressing PI3K/Akt/mTOR. Thus, SK may be a promising antineoplastic drug in Hepatocellular carcinoma (HCC). SK downregulating PYCR1 might supply a theoretical foundation for the potential therapeutic application in hepatocellular carcinoma.

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“…APG-2575 (lisaftoclax) is a BCL-2 selective inhibitor independently developed by Suzhou Ascentage Pharma, several clinical trials have been initiated in hematologic malignancies [ 13 ]. The results of the phase I trial (NCT03537482) showed that APG-2575 had anti-tumor activity and tolerable safety in patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL), small lymphocytic lymphoma (SLL) and other hematologic tumors [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Homoharringtonine is synergistically lethal with BCL-2 inhibitor APG-2575 in acute myeloid leukemia

et al. 2022

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Background Despite advances in targeted agent development, effective treatment of acute myeloid leukemia (AML) remains a major clinical challenge. The B-cell lymphoma-2 (BCL-2) inhibitor exhibited promising clinical activity in AML, acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL) treatment. APG-2575 is a novel BCL-2 selective inhibitor, which has demonstrated anti-tumor activity in hematologic malignancies. Homoharringtonine (HHT), an alkaloid, exhibited anti-AML activity. Methods The synergistic effects of APG-2575 and HHT were studied in AML cell lines and primary samples. MTS was used to measure the cell viability. Annexin V/propidium iodide staining was used to measure the apoptosis rate by flow cytometry. AML cell xenografted mouse models were established to evaluate the anti-leukemic effect of BCL-2 inhibitor, HHT and their combination in vivo. Western blot was used to determine the expression of related proteins. Results APG-2575 showed comparable anti-leukemic effect to the FDA-approved BCL-2 inhibitor ABT-199 in vitro and in vivo. Combined treatment of HHT with APG-2575 synergistically inhibited AML cell growth and engraftment. Mechanistically, HHT promoted degradation of myeloid cell leukemia-1 (MCL-1), which was reported to induce BCL-2 inhibitor resistant, through the PI3K/AKT/GSK3β signaling pathway. Conclusion Our results provide an effective AML treatment strategy through combination of APG-2575 and HHT, which is worthy of further clinical research.

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FLT3 inhibition by olverembatinib (HQP1351) downregulates MCL-1 and synergizes with BCL-2 inhibitor lisaftoclax (APG-2575) in preclinical models of FLT3-ITD mutant acute myeloid leukemia

Cited by 18 publications

References 45 publications

Progress in understanding the mechanisms of resistance to BCL-2 inhibitors

Progress in understanding the mechanisms of resistance to BCL-2 inhibitors

Shikonin induces apoptosis and autophagy via downregulation of pyrroline-5-carboxylate reductase1 in hepatocellular carcinoma cells

Homoharringtonine is synergistically lethal with BCL-2 inhibitor APG-2575 in acute myeloid leukemia

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