MDM2 inhibitor APG-115 exerts potent antitumor activity and synergizes with standard-of-care agents in preclinical acute myeloid leukemia models

Abstract Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous clonal disease associated with unmet medical needs. Paralleling the pathology of other cancers, AML tumorigenesis and propagation can be ascribed to dysregulated cellular processes, including apoptosis. This function...

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Main Authors: Douglas D. Fang, Qiuqiong Tang, Yanhui Kong, Tao Rong, Qixin Wang, Na Li, Xu Fang, Jiaxing Gu, Dengkun Xiong, Yan Yin, Jing Deng, Dajun Yang, Yifan Zhai
Format: Article
Language:English
Published: Nature Publishing Group 2021-05-01
Series:Cell Death Discovery
Online Access:https://doi.org/10.1038/s41420-021-00465-5
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author Douglas D. Fang
Qiuqiong Tang
Yanhui Kong
Tao Rong
Qixin Wang
Na Li
Xu Fang
Jiaxing Gu
Dengkun Xiong
Yan Yin
Jing Deng
Dajun Yang
Yifan Zhai
author_facet Douglas D. Fang
Qiuqiong Tang
Yanhui Kong
Tao Rong
Qixin Wang
Na Li
Xu Fang
Jiaxing Gu
Dengkun Xiong
Yan Yin
Jing Deng
Dajun Yang
Yifan Zhai
author_sort Douglas D. Fang
collection DOAJ
description Abstract Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous clonal disease associated with unmet medical needs. Paralleling the pathology of other cancers, AML tumorigenesis and propagation can be ascribed to dysregulated cellular processes, including apoptosis. This function and others are regulated by tumor suppressor P53, which plays a pivotal role in leukemogenesis. Opposing P53-mediated activities is the mouse double minute 2 homolog (MDM2), which promotes P53 degradation. Because the TP53 mutation rate is low, and MDM2 frequently overexpressed, in patients with leukemia, targeting the MDM2-P53 axis to restore P53 function has emerged as an attractive AML treatment strategy. APG-115 is a potent MDM2 inhibitor under clinical development for patients with solid tumors. In cellular cultures and animal models of AML, we demonstrate that APG-115 exerted substantial antileukemic activity, as either a single agent or when combined with standard-of-care (SOC) hypomethylating agents azacitidine (AZA) and decitabine (DAC), or the DNA-damaging agent cytarabine (Ara-C). By activating the P53/P21 pathway, APG-115 exhibited potent antiproliferative and apoptogenic activities, and induced cell cycle arrest, in TP53 wild-type AML lines. In vivo, APG-115 significantly reduced tumor burden and prolonged survival. Combinations of APG-115 with SOC treatments elicited synergistic antileukemic activity. To explain these effects, we propose that APG-115 and SOC agents augment AML cell killing by complementarily activating the P53/P21 pathway and upregulating DNA damage. These findings and the emerging mechanism of action afford a sound scientific rationale to evaluate APG-115 (with or without SOC therapies) in patients with AML.
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spelling doaj.art-0861a6467ccf4e0d8d9e7c3d5cc9b4a42022-12-21T22:47:22ZengNature Publishing GroupCell Death Discovery2058-77162021-05-017111510.1038/s41420-021-00465-5MDM2 inhibitor APG-115 exerts potent antitumor activity and synergizes with standard-of-care agents in preclinical acute myeloid leukemia modelsDouglas D. Fang0Qiuqiong Tang1Yanhui Kong2Tao Rong3Qixin Wang4Na Li5Xu Fang6Jiaxing Gu7Dengkun Xiong8Yan Yin9Jing Deng10Dajun Yang11Yifan Zhai12Ascentage Pharma (Suzhou) Co., Ltd.Ascentage Pharma (Suzhou) Co., Ltd.Ascentage Pharma (Suzhou) Co., Ltd.Ascentage Pharma (Suzhou) Co., Ltd.Ascentage Pharma (Suzhou) Co., Ltd.Ascentage Pharma (Suzhou) Co., Ltd.Ascentage Pharma (Suzhou) Co., Ltd.Ascentage Pharma (Suzhou) Co., Ltd.Ascentage Pharma (Suzhou) Co., Ltd.Ascentage Pharma (Suzhou) Co., Ltd.Ascentage Pharma (Suzhou) Co., Ltd.Ascentage Pharma (Suzhou) Co., Ltd.Ascentage Pharma (Suzhou) Co., Ltd.Abstract Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous clonal disease associated with unmet medical needs. Paralleling the pathology of other cancers, AML tumorigenesis and propagation can be ascribed to dysregulated cellular processes, including apoptosis. This function and others are regulated by tumor suppressor P53, which plays a pivotal role in leukemogenesis. Opposing P53-mediated activities is the mouse double minute 2 homolog (MDM2), which promotes P53 degradation. Because the TP53 mutation rate is low, and MDM2 frequently overexpressed, in patients with leukemia, targeting the MDM2-P53 axis to restore P53 function has emerged as an attractive AML treatment strategy. APG-115 is a potent MDM2 inhibitor under clinical development for patients with solid tumors. In cellular cultures and animal models of AML, we demonstrate that APG-115 exerted substantial antileukemic activity, as either a single agent or when combined with standard-of-care (SOC) hypomethylating agents azacitidine (AZA) and decitabine (DAC), or the DNA-damaging agent cytarabine (Ara-C). By activating the P53/P21 pathway, APG-115 exhibited potent antiproliferative and apoptogenic activities, and induced cell cycle arrest, in TP53 wild-type AML lines. In vivo, APG-115 significantly reduced tumor burden and prolonged survival. Combinations of APG-115 with SOC treatments elicited synergistic antileukemic activity. To explain these effects, we propose that APG-115 and SOC agents augment AML cell killing by complementarily activating the P53/P21 pathway and upregulating DNA damage. These findings and the emerging mechanism of action afford a sound scientific rationale to evaluate APG-115 (with or without SOC therapies) in patients with AML.https://doi.org/10.1038/s41420-021-00465-5
spellingShingle Douglas D. Fang
Qiuqiong Tang
Yanhui Kong
Tao Rong
Qixin Wang
Na Li
Xu Fang
Jiaxing Gu
Dengkun Xiong
Yan Yin
Jing Deng
Dajun Yang
Yifan Zhai
MDM2 inhibitor APG-115 exerts potent antitumor activity and synergizes with standard-of-care agents in preclinical acute myeloid leukemia models
Cell Death Discovery
title MDM2 inhibitor APG-115 exerts potent antitumor activity and synergizes with standard-of-care agents in preclinical acute myeloid leukemia models
title_full MDM2 inhibitor APG-115 exerts potent antitumor activity and synergizes with standard-of-care agents in preclinical acute myeloid leukemia models
title_fullStr MDM2 inhibitor APG-115 exerts potent antitumor activity and synergizes with standard-of-care agents in preclinical acute myeloid leukemia models
title_full_unstemmed MDM2 inhibitor APG-115 exerts potent antitumor activity and synergizes with standard-of-care agents in preclinical acute myeloid leukemia models
title_short MDM2 inhibitor APG-115 exerts potent antitumor activity and synergizes with standard-of-care agents in preclinical acute myeloid leukemia models
title_sort mdm2 inhibitor apg 115 exerts potent antitumor activity and synergizes with standard of care agents in preclinical acute myeloid leukemia models
url https://doi.org/10.1038/s41420-021-00465-5
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