Dual targeting of BCL2 and MCL1 rescues myeloma cells resistant to BCL2 and MCL1 inhibitors associated with the formation of BAX/ BAK hetero-complexes
| Autor: | Charlotte Kervoëlen, Sophie Maïga, Patricia Gomez-Bougie, Carolane Seiller, Laurent Maillet, Celine Bellanger, Philippe Moreau, Martine Amiot, Catherine Pellat-Deceunynck, Géraldine Descamps, Cyrille Touzeau |
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| Přispěvatelé: | Regulation of Bcl2 and p53 Networks in Multiple Myeloma and Mantle Cell Lymphoma (CRCINA-ÉQUIPE 10), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Site de Recherche Intégrée sur le Cancer - SIRIC « ILIAD » [Nantes] (INCA-DGOS-Inserm), Service d'Hématologie Clinique [CHU Nantes] (Unité d'Investigation Clinique), Centre hospitalier universitaire de Nantes (CHU Nantes), Plate-forme Therassay Onco-Hématologie, Capacités [UN Nantes], Université de Nantes (UN), Stress Adaptation and Tumor Escape in Breast Cancer (CRCINA-ÉQUIPE 8), Integrative Oncogenomics of Multiple Myeloma Pathogenesis and Progression (CRCINA-ÉQUIPE 11), This study was supported by the Fondation Française pour la Recherche contre le Myélome et les Gammapathies monoclonales (FFRMG), Ligue Grand Ouest contre le Cancer, Intergroupe Francophone du Myélome, Action Cancer 44 and the SIRIC ILIAD,INCa-DGOS-Inserm_12558., Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), Bernardo, Elizabeth |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
Programmed cell death Immunology Antineoplastic Agents Apoptosis Myeloma [SDV.CAN]Life Sciences [q-bio]/Cancer Thiophenes Plasma cell Article 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound 0302 clinical medicine [SDV.CAN] Life Sciences [q-bio]/Cancer immune system diseases Cell Line Tumor hemic and lymphatic diseases medicine Humans MCL1 lcsh:QH573-671 Multiple myeloma 030304 developmental biology 0303 health sciences Venetoclax lcsh:Cytology Cell Biology medicine.disease 3. Good health medicine.anatomical_structure Pyrimidines chemistry Proto-Oncogene Proteins c-bcl-2 Cell culture Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Myeloid Cell Leukemia Sequence 1 Protein Neoplasm Recurrence Local Apoptosis Regulatory Proteins Multiple Myeloma Ex vivo |
| Zdroj: | Cell Death and Disease Cell Death and Disease, Nature Publishing Group, 2020, 11, pp.316. ⟨10.1038/s41419-020-2505-1⟩ Cell Death & Disease Cell Death and Disease, Vol 11, Iss 5, Pp 1-14 (2020) Cell Death and Disease, 2020, 11, pp.316. ⟨10.1038/s41419-020-2505-1⟩ |
| ISSN: | 2041-4889 |
| Popis: | Multiple myeloma is a plasma cell malignancy that escapes from apoptosis by heterogeneously over-expressing anti-apoptotic BCL2 proteins. Myeloma cells with a t(11;14) translocation present a particular vulnerability to BCL2 inhibition while a majority of myeloma cells relies on MCL1 for survival. The present study aimed to determine whether the combination of BCL2 and MCL1 inhibitors at low doses could be of benefit for myeloma cells beyond the single selective inhibition of BCL2 or MCL1. We identified that half of patients were not efficiently targeted neither by BCL2 inhibitor nor MCL1 inhibitor. Seventy percent of these myeloma samples, either from patients at diagnosis or relapse, presented a marked increase of apoptosis upon low dose combination of both inhibitors. Interestingly, primary cells from a patient in progression under venetoclax treatment were not sensitive ex vivo to neither venetoclax nor to MCL1 inhibitor, whereas the combination of both efficiently induced cell death. This finding suggests that the combination could overcome venetoclax resistance. The efficacy of the combination was also confirmed in U266 xenograft model resistant to BCL2 and MCL1 inhibitors. Mechanistically, we demonstrated that the combination of both inhibitors favors apoptosis in a BAX/BAK dependent manner. We showed that activated BAX was readily increased upon the inhibitor combination leading to the formation of BAK/BAX hetero-complexes. We found that BCLXL remains a major resistant factor of cell death induced by this combination. The present study supports a rational for the clinical use of venetoclax/S63845 combination in myeloma patients with the potential to elicit significant clinical activity when both single inhibitors would not be effective but also to overcome developed in vivo venetoclax resistance. |
| Databáze: | OpenAIRE |
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