Developmental Regulation of Mitochondrial Apoptosis by c-Myc Governs Age- and Tissue-Specific Sensitivity to Cancer Therapeutics

Sarosiek, Kristopher A.; Fraser, Colin; Muthalagu, Nathiya; Bhola, Patrick; Chang, Wei‐Ting; McBrayer, Samuel K.; Cantlon, Adam; Fisch, Sudeshna; Golomb-Mello, Gail; Ryan, Jeremy; Deng, Jing; Jian, Brian J.; Corbett, Chris; Goldenberg, Marti; Madsen, Joseph R.; Liao, Ronglih; Walsh, Dominic M.; Sedivy, John M.; Murphy, Daniel J.; Carrasco, Daniel R.; Robinson, Shenandoah; Moslehi, Javid; Letaï, Anthony

doi:10.1016/j.ccell.2016.11.011

Cited by 193 publications

(239 citation statements)

References 57 publications

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“…These regulatory mechanisms to BAX activation may be more effective in blocking direct BAX activation and decreasing the activity of BTSA1 in normal cells compared to AML cells providing an applicable therapeutic index as demonstrated in our in vivo studies. Consistent with our data, a recent report demonstrated the insensitivity of most adult healthy somatic tissues to BAX activation by BIM BH3 (Sarosiek et al, 2017). …”

Section: Discussionsupporting

confidence: 93%

Direct Activation of BAX by BTSA1 Overcomes Apoptosis Resistance in Acute Myeloid Leukemia

et al. 2017

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SUMMARY The BCL-2 family protein BAX is a central mediator of apoptosis. Overexpression of anti-apoptotic BCL-2 proteins contributes to tumor development and resistance to therapy by suppressing BAX and its activators. We report the discovery of BTSA1, a pharmacologically optimized BAX activator that binds with high affinity and specificity to the N-terminal activation site and induces conformational changes to BAX leading to BAX-mediated apoptosis. BTSA1-induced BAX activation effectively promotes apoptosis in leukemia cell lines and patient samples while sparing healthy cells. BAX expression levels and cytosolic conformation regulate sensitivity to BTSA1. BTSA1 potently suppressed human acute myeloid leukemia (AML) xenografts and increased host survival without toxicity. This study provides proof-of-concept for direct BAX activation as a treatment strategy in AML.

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Section: Discussionsupporting

confidence: 93%

Direct Activation of BAX by BTSA1 Overcomes Apoptosis Resistance in Acute Myeloid Leukemia

et al. 2017

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“…Of equal importance, BH3 profiling across many tissues showed that, with the exception of certain blood cells, the mitochondria of normal adult cells are not generally primed for apoptosis, leaving an excess of free antiapoptotic proteins relative to their proapoptotic counterparts. This may explain, in part, the favorable therapeutic index exploited by venetoclax in the treatment of BCL-2-dependent cancers (40, 41). Recently, Montero et al described “Dynamic BH3 Profiling” (42), a technique that can be used to predict the response of cancer cells to chemotherapeutic agents, as well as identify agents capable of inducing BCL-2 priming (Fig.…”

Section: Defining Bcl-2 Dependencementioning

confidence: 99%

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

Leverson

Sampath²,

Souers

et al. 2017

Cancer Discovery

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Since the discovery of apoptosis as a form of programmed cell death, targeting the apoptosis pathway to induce cancer cell death has been a high priority goal for cancer therapy. After decades of effort, drug discovery scientists have succeeded in generating small-molecule inhibitors of antiapoptotic BCL-2 family proteins. Innovative medicinal chemistry and structure-based drug design, coupled with a strong fundamental understanding of BCL-2 biology, were essential to the development of BH3 mimetics such as the BCL-2-selective inhibitor venetoclax. We review a number of preclinical studies that have deepened our understanding of BCL-2 biology and facilitated the clinical development of venetoclax.

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“…It is unclear whether the unprimed subpopulation selected in the first round of treatment is genetically or non-genetically distinct from the primed subpopulation that responds to therapy. Non-genetic heterogeneity is observed in BH3 profiles from somatic tissue from healthy mice, where variation in c-Myc expression levels modulate mitochondrial priming between tissues and over time (Sarosiek et al 2017). …”

Section: Molecular Processes Implicated In the Generation Of Cellularmentioning

confidence: 99%

The impact of non-genetic heterogeneity on cancer cell death

Inde

Dixon

2017

Critical Reviews in Biochemistry and Molecular Biology

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The goal of chemotherapy is to induce homogeneous cell death within the population of targeted cancer cells. However, no two cells are exactly alike at the molecular level, and sensitivity to drug-induced cell death therefore varies within a population. Genetic alterations can contribute to this variability and lead to selection for drug resistant clones. However, there is a growing appreciation for the role of non-genetic variation in producing drug tolerant cellular states that exhibit reduced sensitivity to cell death for extended periods of time, from hours to weeks. These cellular states may result from individual variation in epigenetics, gene expression, metabolism and other processes that impact drug mechanism of action or the execution of cell death. Such population-level non-genetic heterogeneity may contribute to treatment failure and provide a cellular ‘substrate’ for the emergence of genetic alterations that confer frank drug resistance.

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Developmental Regulation of Mitochondrial Apoptosis by c-Myc Governs Age- and Tissue-Specific Sensitivity to Cancer Therapeutics

Cited by 193 publications

References 57 publications

Direct Activation of BAX by BTSA1 Overcomes Apoptosis Resistance in Acute Myeloid Leukemia

Direct Activation of BAX by BTSA1 Overcomes Apoptosis Resistance in Acute Myeloid Leukemia

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

The impact of non-genetic heterogeneity on cancer cell death

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