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Cotargeting of BCL2 with Venetoclax and MCL1 with S63845 Is Synthetically Lethal In Vivo in Relapsed Mantle Cell Lymphoma

D. Prukova, L. Andera, Z. Nahacka, J. Karolova, M. Svaton, M. Klanova, O. Havranek, J. Soukup, K. Svobodova, Z. Zemanova, D. Tuskova, E. Pokorna, K. Helman, K. Forsterova, M. Pacheco-Blanco, P. Vockova, A. Berkova, E. Fronkova, M. Trneny, P. Klener,

. 2019 ; 25 (14) : 4455-4465. [pub] 20190419

Language English Country United States

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link   https://www.medvik.cz/link/bmc20025772

Grant support
NV17-28980A MZ0 CEP Register

PURPOSE: Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphomas characterized by (over)expression of BCL2. A BCL2-targeting drug, venetoclax, has promising anticancer activity in MCL. We analyzed molecular mechanisms of venetoclax resistance in MCL cells and tested strategies to overcome it. EXPERIMENTAL DESIGN: We confirmed key roles of proapoptotic proteins BIM and NOXA in mediating venetoclax-induced cell death in MCL. Both BIM and NOXA are, however, differentially expressed in cell lines compared with primary cells. First, NOXA protein is significantly overexpressed in most MCL cell lines. Second, deletions of BIM gene harbored by three commonly used MCL cell lines (JEKO-1, MINO, and Z138) were not found by array comparative genomic hybridization using a validation set of 24 primary MCL samples. RESULTS: We demonstrated that MCL1 and NOXA play important roles in mediating resistance to venetoclax. Consequently, we tested an experimental treatment strategy based on cotargeting BCL2 with venetoclax and MCL1 with a highly specific small-molecule MCL1 inhibitor S63845. The combination of venetoclax and S63845 demonstrated synthetic lethality in vivo on a panel of five patient-derived xenografts established from patients with relapsed MCL with adverse cytogenetics. CONCLUSIONS: Our data strongly support investigation of venetoclax in combination with S63845 as an innovative treatment strategy for chemoresistant MCL patients with adverse cytogenetics in the clinical grounds.

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$a PURPOSE: Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphomas characterized by (over)expression of BCL2. A BCL2-targeting drug, venetoclax, has promising anticancer activity in MCL. We analyzed molecular mechanisms of venetoclax resistance in MCL cells and tested strategies to overcome it. EXPERIMENTAL DESIGN: We confirmed key roles of proapoptotic proteins BIM and NOXA in mediating venetoclax-induced cell death in MCL. Both BIM and NOXA are, however, differentially expressed in cell lines compared with primary cells. First, NOXA protein is significantly overexpressed in most MCL cell lines. Second, deletions of BIM gene harbored by three commonly used MCL cell lines (JEKO-1, MINO, and Z138) were not found by array comparative genomic hybridization using a validation set of 24 primary MCL samples. RESULTS: We demonstrated that MCL1 and NOXA play important roles in mediating resistance to venetoclax. Consequently, we tested an experimental treatment strategy based on cotargeting BCL2 with venetoclax and MCL1 with a highly specific small-molecule MCL1 inhibitor S63845. The combination of venetoclax and S63845 demonstrated synthetic lethality in vivo on a panel of five patient-derived xenografts established from patients with relapsed MCL with adverse cytogenetics. CONCLUSIONS: Our data strongly support investigation of venetoclax in combination with S63845 as an innovative treatment strategy for chemoresistant MCL patients with adverse cytogenetics in the clinical grounds.
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$a Andera, Ladislav $u Biocev, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic. Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic.
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$a Nahacka, Zuzana $u Biocev, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic. Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic.
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$a Karolova, Jana $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic. First Medical Dept., Charles University and General University Hospital, Prague, Czech Republic.
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$a Havranek, Ondrej $u First Medical Dept., Charles University and General University Hospital, Prague, Czech Republic. Biocev, First Faculty of Medicine, Charles University, Vestec, Czech Republic.
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$a Zemanova, Zuzana $u Center for Oncocytogenetics, Institute of Medical Biochemistry and Laboratory Diagnostics, Charles University and General University Hospital, Prague, Czech Republic.
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$a Pokorna, Eva $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
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$a Helman, Karel $u Faculty of Informatics and Statistics, University of Economics, Prague, Czech Republic. $7 xx0260953
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$a Forsterova, Kristina $u First Medical Dept., Charles University and General University Hospital, Prague, Czech Republic.
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$a Pacheco-Blanco, Mariana $u Biocev, First Faculty of Medicine, Charles University, Vestec, Czech Republic.
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$a Vockova, Petra $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic. First Medical Dept., Charles University and General University Hospital, Prague, Czech Republic.
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$a Fronkova, Eva $u CLIP - Childhood Leukaemia Investigation Prague, Dept. of Paediatric Haematology/Oncology, Second Faculty of Medicine and Charles University Hospital in Motol, Prague, Czech Republic.
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$a Trneny, Marek $u First Medical Dept., Charles University and General University Hospital, Prague, Czech Republic.
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$a Klener, Pavel $u Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic. pavel.klener@gmail.com. First Medical Dept., Charles University and General University Hospital, Prague, Czech Republic.
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