期刊
MOLECULAR CANCER THERAPEUTICS
卷 21, 期 1, 页码 89-99出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-21-0511
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- Charles University [PRIMUS 19/MED/07]
- Ministry of Health of the Czech Republic [NU21-03-00386]
- Grant Agency of the Czech Republic [GA20-25308S, GA19-08772S]
- Charles University Center of Excellence [UNCE/MED/016]
- Ministry of Education, Youth and Sports [PROGRES Q26/LF1, PROGRES Q28/LF1]
MCL1 is a critical survival molecule for most Burkitt lymphomas and a subset of BCL2-negative DLBCLs. The levels of BCL2 and MCL1 expression and the occupational status of MCL1 are key factors in modulating sensitivity/resistance to S63845.
The pro-survival MCL1 protein is overexpressed in many S63845 is a highly specific inhibitor of MCL1. We analyzed models of diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma. Annexin V-based cytotoxic assays, Western blot analysis, protein co-immunoprecipitation, and cell clones with manipulated expression of BCL2 family proteins were used to analyze mechanisms of sensitivity to S63845. Experimental in vivo therapy with S63845 and/or venetoclax was performed using patient-derived xenografts (PDX) of treatment-refractory B-NHL. A subset of DLBCL and majority of Burkitt lymphoma cell lines were sensitive to S63845. The level of BCL2 protein expression was the major determinant of resistance to S63845: BCL2 serves as a buffer for pro-apoptotic proteins released from MCL1 upon exposure to S63845. While BCL2-negative lympho-mas were effectively eliminated by single-agent S63845, its combination with venetoclax was synthetically lethal in BCL2-positive PDX models. Concerning MCL1, both, the level of MCL1 protein expression, and its occupational status represent key factors mediating sensitivity to S63845. In contrast to MCL1-BIM/BAK1 complexes that prime lymphoma cells for S63845-mediated apoptosis, MCL1-NOXA complexes are associated with S63845 resistance. In conclusion, MCL1 represents a critical survival molecule for most Burkitt lymphomas and a subset of BCL2-negative DLBCLs. The level of BCL2 and MCL1 expression and occupational status of MCL1 belong to the key modulators of sensitivity/resistance to S63845. Co-treatment with venetoclax can overcome BCL2-mediated resistance to S63845, and enhance efficacy of MCL1 inhibitors in BCL2-positive aggressive B-NHL.
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