Humanized <i>Mcl-1</i> mice enable accurate pre-clinical evaluation of MCL-1 inhibitors destined for clinical use

Brennan, Margs S.; Chang, Catherine; Dewson, Grant; Tai, Lin; Lessène, Guillaume; Strasser, Andreas; Kelly, Gemma L.; Herold, Marco J.

doi:10.1101/335430

Cited by 4 publications

(5 citation statements)

References 30 publications

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“…3e). While the trend for the higher efficacy of single agent MCL1 vs. BCL2 inhibition is consistent with our in vitro results, the limited affinity of S63845 for murine MCL1 22,27 may mask otherwise stronger effects in this murine GEMM. In addition, S63845/chemotherapy regimens induced pronounced weight loss indicating high toxicity for the combination that prohibited a dose escalation for the MCL1 inhibitor (Supplementary Fig.…”

Section: Resultssupporting

confidence: 89%

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MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer

et al. 2019

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MYC paralogs are frequently activated in small cell lung cancer (SCLC) but represent poor drug targets. Thus, a detailed mapping of MYC -paralog-specific vulnerabilities may help to develop effective therapies for SCLC patients. Using a unique cellular CRISPR activation model, we uncover that, in contrast to MYCN and MYCL, MYC represses BCL2 transcription via interaction with MIZ1 and DNMT3a. The resulting lack of BCL2 expression promotes sensitivity to cell cycle control inhibition and dependency on MCL1. Furthermore, MYC activation leads to heightened apoptotic priming, intrinsic genotoxic stress and susceptibility to DNA damage checkpoint inhibitors. Finally, combined AURK and CHK1 inhibition substantially prolongs the survival of mice bearing MYC-driven SCLC beyond that of combination chemotherapy. These analyses uncover MYC -paralog-specific regulation of the apoptotic machinery with implications for genotype-based selection of targeted therapeutics in SCLC patients.

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Section: Resultssupporting

confidence: 89%

“…3a). Despite a lower activity against murine MCL1 27 , we observed an increased susceptibility to S63845 only in Myc but not in Mycn - or Mycl -activated CRISPRa cells (Fig. 3e).…”

Section: Resultsmentioning

confidence: 82%

MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer

et al. 2019

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“…Engineered mice displayed greater sensitivity to S63845 treatment (as evidenced by its ability to inhibit tumorigenesis) than wild-type mice but did prompt the transient reduction of B cells in the blood, spleen, and bone marrow. In addition, the study also noted a non-significant reduction in neutrophil levels in the bone marrow [158].…”

Section: Accepted Articlementioning

confidence: 73%

“…Given that S63845 displayed a higher affinity to human MCL1 than mouse MCL1, Brennan et al evaluated efficacy and tolerability in a mouse model expressing human MCL1 [158]. Engineered mice displayed greater sensitivity to S63845 treatment (as evidenced by its ability to inhibit tumorigenesis) than wild-type mice but did prompt the transient reduction of B cells in the blood, spleen, and bone marrow.…”

Section: Accepted Articlementioning

confidence: 99%

Understanding MCL1: from cellular function and regulation to pharmacological inhibition

et al. 2021

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Myeloid cell leukemia-1 (MCL1), an anti-apoptotic member of the BCL2 family characterized by a short half-life, functions as a rapid sensor that regulates cell death and other relevant processes that include cell cycle progression and mitochondrial homeostasis. In cancer, MCL1 overexpression contributes to cell survival and resistance to diverse chemotherapeutic agents; for this reason, several MCL1 inhibitors are currently under preclinical and clinical development for cancer treatment. However, the non-apoptotic functions of MCL1 may influence their therapeutic potential. Overall, the complexity of MCL1 regulation and function represent challenges to the clinical application of MCL1 inhibitors. We now summarize the current knowledge regarding MCL1 structure, regulation, and function that could impact the clinical success of MCL1 inhibitors.

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“…In mice, MCL-1 inhibitor S63845 was tolerated well at concentrations that killed cancer cells, 96 even when murine MCL-1 was replaced by its human ortholog, thereby increasing inhibitor sensitivity of all cells. 108 This may yield a therapeutic window for targeting MCL-1, especially if MCL-1 inhibitors are combined with existing treatments that increase pro-apoptotic protein expression.…”

Section: Overcoming Apoptosis Resistance: Bcl-2 Proteins As Therapeutic Targets In MMmentioning

confidence: 99%

A matter of life or death: targeting MCL-1 in multiple myeloma

Slomp¹

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Activation of caspases through the intrinsic apoptosis pathway is dependent on mitochondrial outer membrane permeabilization (MOMP) by BAX and BAK (Figure 2). This results in leakage of cytochrome C, which activates caspase activator APAF1. 20 To explain the mechanism of BAX and BAK activation, three models of interactions between BCL-2 proteins have been described. 21 According to the direct activation model, some BH3-only proteins ('activators') directly bind and activate effectors BAX and BAK. Other BH3-only proteins ('sensitizers') are unable to do this, but in turn function by binding to pro-survival proteins, which then release bound activators. In the indirect activation model, BH3-only proteins solely function as neutralizers of pro-survival proteins, which then release BAX and BAK. As a result, BAX and BAK are activated spontaneously or by an unknown modification, which leads to apoptosis. These two models are not mutually exclusive, and currently a third and unified model is considered most likely. In this unified model, pro-survival proteins sequester both BH3-only proteins and BAX and BAK. When upregulated, BH3-only proteins act by neutralizing prosurvival proteins as well as by activating BAX and BAK, leading to MOMP and subsequent caspase activation. 21,22 The common factor among all BCL-2 family proteins is the presence of BH domains (Figure 3). BH3-only proteins are named thus because they only contain a BH3-domain. Pro-survival BCL-2 proteins, as well as BAX and BAK, contain four BH domains and therefore have a similar overall structure. 21,23 Most BCL-2 proteins contain a transmembrane domain that allows them to localize to intracellular membranes. In some cases, BCL-2 proteins can receive protein modifications that lead to differences in activity, binding affinity, or degradation. 24 MCL-1 is exemplary in this regard, as it is the only BCL-2 family member whose N-terminal tail is rich in putative and experimentally confirmed modification sites, which are targets for phosphorylation, ubiquitination, and cleavage. 25 Pro-apoptotic BH3-only proteinsBH3-only proteins are sensors of cellular stress. Under unstressed conditions, the expression level of many BH3-only proteins is low. Signals such as cytokine deprivation, DNA-damage, ER stress, hypoxia, and anoikis lead to transcriptional or post-translational upregulation of BH3-only proteins. 26 BH3-only proteins have distinct yet overlapping functions, and their expression depends on cell type and cytotoxic condition. 26 For example, BIM can be transcriptionally induced by FOXO3a upon cytokine deprivation, and phosphorylation of BIM can either increase or decrease its activity, depending on the site. BIM regulates apoptosis of

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Humanized Mcl-1 mice enable accurate pre-clinical evaluation of MCL-1 inhibitors destined for clinical use

Cited by 4 publications

References 30 publications

MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer

MYC paralog-dependent apoptotic priming orchestrates a spectrum of vulnerabilities in small cell lung cancer

Understanding MCL1: from cellular function and regulation to pharmacological inhibition

A matter of life or death: targeting MCL-1 in multiple myeloma

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