Humanized Mcl-1 mice enable accurate pre-clinical evaluation of MCL-1 inhibitors destined for clinical use
Publication Year 2018-10, Volume 132, Issue #15, Page 1573-1583
- Journal Title
- Publication Type
- Journal Article
- MCL-1 (myeloid cell leukemia-1) is a pro-survival BCL-2 family member required for the sustained growth of many cancers. Recently a highly specific MCL-1-inhibitor, S63845, showing 6-fold higher affinity to human compared to mouse MCL-1 has been described. To accurately test efficacy and tolerability of this BH3 mimetic drug in pre-clinical cancer models, we developed a humanized Mcl-1 (huMcl-1) mouse strain in which MCL-1 was replaced with its human homolog. HuMcl-1 mice are phenotypically indistinguishable from wild-type mice but are more sensitive to the MCL-1 inhibitor S63845. Importantly, non-transformed cells and lymphomas from huMcl-1;Emicro-Myc mice are more sensitive to S63845 in vitro than their control counterparts. When huMcl-1;Emicro-Myc lymphoma cells were transplanted into huMcl-1 mice, treatment with S63845 alone or alongside cyclophosphamide led to long-term remission in ~60% or almost 100% of mice, respectively. These results demonstrate the potential of our huMCL-1 mouse model for testing MCL-1 inhibitors, allowing precise predictions of efficacy and tolerability for clinical translation.
- WEHI Research Division(s)
- Cell Signalling And Cell Death; Molecular Genetics Of Cancer; Chemical Biology
- PubMed ID
- Publisher's Version
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- Refer to copyright notice on published article.
Creation Date: 2018-08-27 09:10:42Last Modified: 2018-10-22 10:05:29