Re-inforcing the cell death army in the fight against breast cancer

Oudenaarden, Clara; Ven, Robert A. H. van de; Derksen, Patrick W.B.

doi:10.1242/jcs.212563

Cited by 20 publications

(14 citation statements)

References 119 publications

(164 reference statements)

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“…Since the approval of venetoclax for chronic lymphocytic leukemia, BH3 mimetics have bloomed as potential treatments for multiple types of cancer, predominantly hematological ( Valentin et al, 2018 ). Despite impressive experimental and clinical results as single agents, increasing evidence showed that BH3 mimetics real potential is enhancing other anti-cancer agents, both conventional chemotherapy and targeted ( Montero and Letai, 2018 ; Oudenaarden et al, 2018 ; Savona and Wei, 2019 ; Lin et al, 2020 ). Numerous studies have demonstrated that cancer cells often rely on anti-apoptotic proteins to acquire resistance to therapy, and BH3 mimetics can effectively block these adaptations ( Hata et al, 2015 ; Maji et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

MCL-1 Inhibition Overcomes Anti-apoptotic Adaptation to Targeted Therapies in B-Cell Precursor Acute Lymphoblastic Leukemia

Manzano-Muñoz

Alcon

Menéndez

et al. 2021

Front. Cell Dev. Biol.

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Multiple targeted therapies are currently explored for pediatric and young adult B-cell precursor acute lymphoblastic leukemia (BCP-ALL) treatment. However, this new armamentarium of therapies faces an old problem: choosing the right treatment for each patient. The lack of predictive biomarkers is particularly worrying for pediatric patients since it impairs the implementation of new treatments in the clinic. In this study, we used the functional assay dynamic BH3 profiling (DBP) to evaluate two new treatments for BCP-ALL that could improve clinical outcome, especially for relapsed patients. We found that the MEK inhibitor trametinib and the multi-target tyrosine kinase inhibitor sunitinib exquisitely increased apoptotic priming in an NRAS-mutant and in a KMT2A-rearranged cell line presenting a high expression of FLT3, respectively. Following these observations, we sought to study potential adaptations to these treatments. Indeed, we identified with DBP anti-apoptotic changes in the BCL-2 family after treatment, particularly involving MCL-1 – a pro-survival strategy previously observed in adult cancers. To overcome this adaptation, we employed the BH3 mimetic S63845, a specific MCL-1 inhibitor, and evaluated its sequential addition to both kinase inhibitors to overcome resistance. We observed that the metronomic combination of both drugs with S63845 was synergistic and showed an increased efficacy compared to single agents. Similar observations were made in BCP-ALL KMT2A-rearranged PDX cells in response to sunitinib, showing an analogous DBP profile to the SEM cell line. These findings demonstrate that rational sequences of targeted agents with BH3 mimetics, now extensively explored in clinical trials, may improve treatment effectiveness by overcoming anti-apoptotic adaptations in BCP-ALL.

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Section: Discussionmentioning

confidence: 99%

MCL-1 Inhibition Overcomes Anti-apoptotic Adaptation to Targeted Therapies in B-Cell Precursor Acute Lymphoblastic Leukemia

Manzano-Muñoz

Alcon

Menéndez

et al. 2021

Front. Cell Dev. Biol.

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“…If apoptosis is inhibited, however, then cells that are extruded can survive to form disorganized tissue masses. In tubular organs such as the breast this can result in occlusion of the lumens, as occurs with ductal carcinoma in situ [6,7].…”

Section: Introductionmentioning

confidence: 99%

Polarity proteins in oncogenesis

Fomicheva

Tross

Macara

2020

Current Opinion in Cell Biology

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Most human cancers arise from epithelial tissues, which are apical-basally polarized and possess intercellular adhesive junctions. Epithelial cells grow to characteristic densities, often from proliferative progenitors, which arrest as they mature. Homeostatic mechanisms can maintain this characteristic density if it is exceeded (crowding) or is too low (e.g., in response to wounding). During tumor initiation and progression this homeostatic mechanism is lost. Some aspects of cell polarity are also lost, although many carcinomas retain intercellular junctions and even apical domains. In other cases, and particularly in recurrent tumors, however, the cells become predominantly mesenchymal. A major question, still only incompletely answered, is whether the proteins that determine cell polarity function as tumor suppressors or tumor promoters. Here we discuss recent advances in understanding the role of polarity proteins and homeostasis in cancer.

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“…The release of the BH3-only protein enables the activation of the Bax/Bak proteins [143] (Figure 6). Anti-estrogens and other agents used in ER+ breast cancer treatment such as PI3K/mTOR inhibitors and chemotherapeutics have been reported to upregulate Bcl-2 proteins, priming the cell for BH3 mimetic activity [114,130,144].…”

Section: Mitochondrial Priming For Bh3 Mimetic Activitymentioning

confidence: 99%

Regulation of Bcl-2 Family Proteins in Estrogen Receptor-Positive Breast Cancer and Their Implications in Endocrine Therapy

Kawiak

Kostecka

2022

Cancers

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Estrogen receptor (ER)-positive breast cancer accounts for around two-thirds of breast cancer occurrences, with endocrine therapy serving as first-line therapy in most cases. Targeting estrogen signaling pathways, which play a central role in regulating ER+ breast cell proliferation and survival, has proven to improve patient outcomes. However, despite the undeniable advantages of endocrine therapy, a subset of breast cancer patients develop acquired or intrinsic resistance to ER-targeting agents, limiting their efficacy. The activation of downstream ER signaling pathways upregulates pro-survival mechanisms that have been shown to influence the response of cells to endocrine therapy. The Bcl-2 family proteins play a central role in cell death regulation and have been shown to contribute to endocrine therapy resistance, supporting the survival of breast cancer cells and enhancing cell death evasion. Due to the overexpression of anti-apoptotic Bcl-2 proteins in ER-positive breast cancer, the role of these proteins as potential targets in hormone-responsive breast cancer is growing in interest. In particular, recent advances in the development of BH3 mimetics have enabled their evaluation in preclinical studies with ER+ breast cancer models, and BH3 mimetics have entered early ER+ breast cancer clinical trials. This review summarizes the molecular mechanisms underlying the regulation of Bcl-2 family proteins in ER+ breast cancer. Furthermore, an overview of recent advances in research regarding the efficacy of BH3 mimetics in ER+ breast cancer has been provided.

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Re-inforcing the cell death army in the fight against breast cancer

Cited by 20 publications

References 119 publications

MCL-1 Inhibition Overcomes Anti-apoptotic Adaptation to Targeted Therapies in B-Cell Precursor Acute Lymphoblastic Leukemia

MCL-1 Inhibition Overcomes Anti-apoptotic Adaptation to Targeted Therapies in B-Cell Precursor Acute Lymphoblastic Leukemia

Polarity proteins in oncogenesis

Regulation of Bcl-2 Family Proteins in Estrogen Receptor-Positive Breast Cancer and Their Implications in Endocrine Therapy

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