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

Abstract

SUMMARY It is not understood why healthy tissues can exhibit varying levels of sensitivity to the same toxic stimuli. Using BH3 Profiling, we find that mitochondria of many adult somatic tissues, including brain, heart and kidneys, are profoundly refractory to pro-apoptotic signaling, leading to cellular resistance to cytotoxic chemotherapies and ionizing radiation. In contrast, mitochondria from these tissues in young mice and humans are primed for apoptosis, predisposing them to undergo cell death in response to genotoxic damage. While expression of the apoptotic protein machinery is nearly absent by adulthood, in young tissues its expression is driven by c-Myc, linking developmental growth to cell death. These differences may explain why pediatric cancer patients have a higher risk of developing treatment-associated toxicities.

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

“…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). …”

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

“…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.…”

The impact of non-genetic heterogeneity on cancer cell death

“…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). …”