2. Academic Validation
  3. Cotargeting of BCL2 with Venetoclax and MCL1 with S63845 Is Synthetically Lethal In Vivo in Relapsed Mantle Cell Lymphoma

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

  • Clin Cancer Res. 2019 Jul 15;25(14):4455-4465. doi: 10.1158/1078-0432.CCR-18-3275.
Dana Prukova 1,  Ladislav Andera 2 3,  Zuzana Nahacka 2 3,  Jana Karolova 1 4,  Michael Svaton 5,  Magdalena Klanova 1 4,  Ondrej Havranek 4 6,  Jan Soukup 7,  Karla Svobodova 8,  Zuzana Zemanova 8,  Diana Tuskova 1 4,  Eva Pokorna 1,  Karel Helman 9,  Kristina Forsterova 4,  Mariana Pacheco-Blanco 6,  Petra Vockova 1 4,  Adela Berkova 8,  Eva Fronkova 5,  Marek Trneny 4,  Pavel Klener 10 4
Affiliations

Affiliations

  • 1 Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic.
  • 2 Biocev, Institute of Biotechnology, Czech Academy of Sciences, Vestec, Czech Republic.
  • 3 Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic.
  • 4 First Medical Dept., Charles University and General University Hospital, Prague, Czech Republic.
  • 5 CLIP - Childhood Leukaemia Investigation Prague, Dept. of Paediatric Haematology/Oncology, Second Faculty of Medicine and Charles University Hospital in Motol, Prague, Czech Republic.
  • 6 Biocev, First Faculty of Medicine, Charles University, Vestec, Czech Republic.
  • 7 Department of Pathology and Molecular Medicine, Second Faculty of Medicine and Charles University Hospital in Motol, Prague, Czech Republic.
  • 8 Center for Oncocytogenetics, Institute of Medical Biochemistry and Laboratory Diagnostics, Charles University and General University Hospital, Prague, Czech Republic.
  • 9 Faculty of Informatics and Statistics, University of Economics, Prague, Czech Republic.
  • 10 Institute of Pathological Physiology, First Faculty of Medicine, Charles University, Prague, Czech Republic. pavel.klener@gmail.com.
PMID: 31004002 DOI: 10.1158/1078-0432.CCR-18-3275
Abstract

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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