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Venetoclax resistance leads to broad resistance to standard-of-care anti-MM agents, but not to immunotherapies.
- Source :
-
Blood advances [Blood Adv] 2024 Aug 13; Vol. 8 (15), pp. 4025-4034. - Publication Year :
- 2024
-
Abstract
- Abstact: To our knowledge, venetoclax is the first example of personalized medicine for multiple myeloma (MM), with meaningful clinical activity as a monotherapy and in combination in patients with myeloma harboring the t(11:14) translocation. However, despite the high response rates and prolonged progression-free survival, a significant proportion of patients eventually relapse. Here, we aim to study adaptive molecular responses after the acquisition of venetoclax resistance in sensitive t(11:14) MM cell models. We therefore generated single-cell venetoclax-resistant t(11:14) MM cell lines and investigated the mechanisms contributing to resistance as well as the cells' sensitivity to other treatments. Our data suggest that acquired resistance to venetoclax is characterized by reduced mitochondrial priming and changes in B-cell lymphoma-2 (BCL-2) family proteins' expression in MM cells, conferring broad resistance to standard-of-care antimyeloma drugs. However, our results show that the resistant cells are still sensitive to immunotherapeutic treatments, highlighting the need to consider appropriate sequencing of these treatments after venetoclax-based regimens.<br /> (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Subjects :
- Humans
Cell Line, Tumor
Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors
Proto-Oncogene Proteins c-bcl-2 metabolism
Bridged Bicyclo Compounds, Heterocyclic therapeutic use
Bridged Bicyclo Compounds, Heterocyclic pharmacology
Sulfonamides therapeutic use
Sulfonamides pharmacology
Drug Resistance, Neoplasm
Multiple Myeloma drug therapy
Multiple Myeloma therapy
Antineoplastic Agents therapeutic use
Antineoplastic Agents pharmacology
Immunotherapy methods
Subjects
Details
- Language :
- English
- ISSN :
- 2473-9537
- Volume :
- 8
- Issue :
- 15
- Database :
- MEDLINE
- Journal :
- Blood advances
- Publication Type :
- Academic Journal
- Accession number :
- 38861273
- Full Text :
- https://doi.org/10.1182/bloodadvances.2023012298