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Klanova, M.* ; Kazantsev, D.* ; Pokorna, E.* ; Zikmund, T. ; Karolova, J.* ; Behounek, M.* ; Renesova, N.* ; Sovilj, D.* ; Kelemen, C.D.* ; Helman, K.* ; Jaksa, R.* ; Havranek, O.* ; Andera, L.* ; Trneny, M.* ; Klener, P.*

Anti-apoptotic MCL1 protein represents critical survival molecule for most Burkitt lymphomas and BCL2-negative diffuse large B-cell lymphomas.

Mol. Cancer Ther. 21, 89-99 (2021)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
The pro-survival MCL1 protein is overexpressed in many cancers, including B-cell non-Hodgkin lymphomas (B-NHL). S63845 is a highly specific inhibitor of MCL1. We analyzed mechanisms of sensitivity/resistance to S63845 in preclinical models of diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL). Annexin V-based cytotoxic assays, western blot, 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 BL 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 lymphomas 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 BLs 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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Gene-expression; Elderly-patients; Bcl-2 Family; Venetoclax; Chemotherapy; Inhibition; Mutations; Subgroups; Abt-199; Dlbcl
ISSN (print) / ISBN 1535-7163
e-ISSN 1538-8514
Zeitschrift Molecular Cancer Therapeutics
Quellenangaben Band: 21, Heft: 1, Seiten: 89-99 Artikelnummer: , Supplement: ,
Verlag American Association for Cancer Research (AACR)
Verlagsort 615 Chestnut St, 17th Floor, Philadelphia, Pa 19106-4404 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Epigenetics and Stem Cells (IES)
Förderungen Ministry of Education, Youth and Sports
Charles University Center of Excellence
Grant Agency of the Czech Republic
Ministry of Health of the Czech Republic
Charles University