Co-targeting BCL-XL and BCL-2 by PROTAC 753B eliminates leukemia cells and enhances efficacy of chemotherapy by targeting senescent cells

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Abstract

BCL-X _L and BCL-2 are key anti-apoptotic proteins and validated cancer targets. 753B is a novel BCL-X _L/BCL-2 proteolysis targeting chimera (PROTAC) that targets both BCL-X _L and BCL-2 to the von Hippel-Lindau (VHL) E3 ligase, leading to BCL-X _L/BCL-2 ubiquitination and degradation selectively in cells expressing VHL. Because platelets lack VHL expression, 753B spares on-target platelet toxicity caused by the first-generation dual BCL-X _L/BCL-2 inhibitor navitoclax (ABT-263). Here, we report pre-clinical single-agent activity of 753B against different leukemia subsets. 753B effectively reduced cell viability and induced dose-dependent degradation of BCL-X _L and BCL-2 in a subset of hematopoietic cell lines, acute myeloid leukemia (AML) primary samples, and in vivo patient-derived xenograft AML models. We further demonstrated the senolytic activity of 753B, which enhanced the efficacy of chemotherapy by targeting chemotherapy-induced cellular senescence. These results provide a pre-clinical rationale for the utility of 753B in AML therapy, and suggest that 753B could produce an added therapeutic benefit by overcoming cellular senescence-induced chemoresistance when combined with chemotherapy.

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The senescence-associated secretory phenotype: the dark side of tumor suppression.

Jean-Philippe Coppe, Pierre-Yves Desprez, Ana Krtolica … (2010)

Cellular senescence is a tumor-suppressive mechanism that permanently arrests cells at risk for malignant transformation. However, accumulating evidence shows that senescent cells can have deleterious effects on the tissue microenvironment. The most significant of these effects is the acquisition of a senescence-associated secretory phenotype (SASP) that turns senescent fibroblasts into proinflammatory cells that have the ability to promote tumor progression.

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Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors

Yi Zhu, Tamara Tchkonia, Heike Fuhrmann-Stroissnigg … (2016)

Summary Clearing senescent cells extends healthspan in mice. Using a hypothesis‐driven bioinformatics‐based approach, we recently identified pro‐survival pathways in human senescent cells that contribute to their resistance to apoptosis. This led to identification of dasatinib (D) and quercetin (Q) as senolytics, agents that target some of these pathways and induce apoptosis preferentially in senescent cells. Among other pro‐survival regulators identified was Bcl‐xl. Here, we tested whether the Bcl‐2 family inhibitors, navitoclax (N) and TW‐37 (T), are senolytic. Like D and Q, N is senolytic in some, but not all types of senescent cells: N reduced viability of senescent human umbilical vein epithelial cells (HUVECs), IMR90 human lung fibroblasts, and murine embryonic fibroblasts (MEFs), but not human primary preadipocytes, consistent with our previous finding that Bcl‐xl siRNA is senolytic in HUVECs, but not preadipocytes. In contrast, T had little senolytic activity. N targets Bcl‐2, Bcl‐xl, and Bcl‐w, while T targets Bcl‐2, Bcl‐xl, and Mcl‐1. The combination of Bcl‐2, Bcl‐xl, and Bcl‐w siRNAs was senolytic in HUVECs and IMR90 cells, while combination of Bcl‐2, Bcl‐xl, and Mcl‐1 siRNAs was not. Susceptibility to N correlated with patterns of Bcl‐2 family member proteins in different types of human senescent cells, as has been found in predicting response of cancers to N. Thus, N is senolytic and acts in a potentially predictable cell type‐restricted manner. The hypothesis‐driven, bioinformatics‐based approach we used to discover that dasatinib (D) and quercetin (Q) are senolytic can be extended to increase the repertoire of senolytic drugs, including additional cell type‐specific senolytic agents.

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Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse.

Marco Demaria, Monique O’Leary, Jianhui Chang … (2017)

Cellular senescence suppresses cancer by irreversibly arresting cell proliferation. Senescent cells acquire a proinflammatory senescence-associated secretory phenotype. Many genotoxic chemotherapies target proliferating cells nonspecifically, often with adverse reactions. In accord with prior work, we show that several chemotherapeutic drugs induce senescence of primary murine and human cells. Using a transgenic mouse that permits tracking and eliminating senescent cells, we show that therapy-induced senescent (TIS) cells persist and contribute to local and systemic inflammation. Eliminating TIS cells reduced several short- and long-term effects of the drugs, including bone marrow suppression, cardiac dysfunction, cancer recurrence, and physical activity and strength. Consistent with our findings in mice, the risk of chemotherapy-induced fatigue was significantly greater in humans with increased expression of a senescence marker in T cells prior to chemotherapy. These findings suggest that senescent cells can cause certain chemotherapy side effects, providing a new target to reduce the toxicity of anticancer treatments.

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Author and article information

Journal

Journal ID (nlm-ta): Haematologica

Journal ID (iso-abbrev): Haematologica

Journal ID (publisher-id): HAEMA

Title: Haematologica

Publisher: Fondazione Ferrata Storti

ISSN (Print): 0390-6078

ISSN (Electronic): 1592-8721

Publication date (Electronic): 20 April 2023

Publication date Collection: 01 October 2023

Volume: 108

Issue: 10

Pages: 2626-2638

Affiliations

[1 ]Department of Leukemia, The University of Texas MD Anderson Cancer Center , Houston, TX, USA

[2 ]Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai, China

[3 ]Hematology Research Unit Helsinki, University of Helsinki and Helsinki University Hospital Comprehensive Cancer Center , Helsinki, Finland

[4 ]Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki , Helsinki, Finland

[5 ]iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland

[6 ]Department of Medicinal Chemistry, College of Pharmacy, University of Florida , Gainesville, FL, USA

[7 ]Department of Biochemistry and Structural Biology and Center for Innovative Drug Discovery, Long School of Medicine, University of Texas Health Science Center at San Antonio , San Antonio, TX, USA

Author notes

M. Konopleva mkonople@ 123456mdanderson.org

Q. Zhang qzhang9@ 123456mdanderson.org

Disclosures

GZ and DZ are co-founders of and have equity in Dialectic Therapeutics, which develops BCL-XL PROTAC to treat cancer. The other authors have no conflict of interests to disclose.

Contributions

YJ conceived, designed and performed most of the biological and biochemical experiments, analyzed and interpreted data, and wrote the manuscript. LH, CR, ZW, CW, LY, SC and HM performed and analyzed some of the biological experiments. WZ, MA, ND, NJ, NP, KB and SM supervised some of the biological studies and revised the manuscript. PZ synthesized 753B, and prepared the formulation of vehicle and 753B for animal study. GZ conceived, designed and supervised the synthesis of BCL-XL/2 PROTAC, and revised the manuscript. DZ conceived, designed and supervised the synthesis of BCL-XL/2 PROTAC, revised the manuscript, and guided senescence studies. QZ and MK conceived, designed, and supervised the study, analyzed and interpreted data, and wrote the manuscript. All authors discussed the results and commented on the manuscript.

Data-sharing statement

Original data and protocols are available to other investigators upon request by contacting the corresponding author or last author.

Article

DOI: 10.3324/haematol.2022.281915

PMC ID: 10542840

PubMed ID: 37078252

SO-VID: f3d35106-f889-481c-b720-71dcf4252426

License:

This article is distributed under the terms of the Creative Commons Attribution Noncommercial License ( by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

History

Date received : 22 August 2022

Date accepted : 07 April 2023

Page count

Figures: 6, Tables: 0, Equations: 0, References: 47, Pages: 13

Funding

Funding: This study was supported by US National Institutes of Health (NIH) grants R01 CA241191 (to GZ, MK and DZ), the Cancer Foundation Finland, and the Academy of Finland (to SM).

Co-targeting BCL-XL and BCL-2 by PROTAC 753B eliminates leukemia cells and enhances efficacy of chemotherapy by targeting senescent cells

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Most cited references 47

The senescence-associated secretory phenotype: the dark side of tumor suppression.

Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors

Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse.

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