CD52 and OXPHOS-potential targets in ibrutinib-treated mantle cell lymphoma
Please always quote using this URN: urn:nbn:de:bvb:20-opus-300817
- Altered features of tumor cells acquired across therapy can result in the survival of treatment-resistant clones that may cause minimal residual disease (MRD). Despite the efficacy of ibrutinib in treating relapsed/refractory mantle cell lymphoma, the obstacle of residual cells contributes to relapses of this mature B-cell neoplasm, and the disease remains incurable. RNA-seq analysis of an ibrutinib-sensitive mantle cell lymphoma cell line following ibrutinib incubation of up to 4 d, corroborated our previously postulated resistance mechanismAltered features of tumor cells acquired across therapy can result in the survival of treatment-resistant clones that may cause minimal residual disease (MRD). Despite the efficacy of ibrutinib in treating relapsed/refractory mantle cell lymphoma, the obstacle of residual cells contributes to relapses of this mature B-cell neoplasm, and the disease remains incurable. RNA-seq analysis of an ibrutinib-sensitive mantle cell lymphoma cell line following ibrutinib incubation of up to 4 d, corroborated our previously postulated resistance mechanism of a metabolic switch to reliance on oxidative phosphorylation (OXPHOS) in surviving cells. Besides, we had shown that treatment-persisting cells were characterized by increased CD52 expression. Therefore, we hypothesized that combining ibrutinib with another agent targeting these potential escape mechanisms could minimize the risk of survival of ibrutinib-resistant cells. Concomitant use of ibrutinib with OXPHOS-inhibitor IACS-010759 increased toxicity compared to ibrutinib alone. Targeting CD52 was even more efficient, as addition of CD52 mAb in combination with human serum following ibrutinib pretreatment led to rapid complement-dependent-cytotoxicity in an ibrutinib-sensitive cell line. In primary mantle cell lymphoma cells, a higher toxic effect with CD52 mAb was obtained, when cells were pretreated with ibrutinib, but only in an ibrutinib-sensitive cohort. Given the challenge of treating multi-resistant mantle cell lymphoma patients, this work highlights the potential use of anti-CD52 therapy as consolidation after ibrutinib treatment in patients who responded to the BTK inhibitor to achieve MRD negativity and prolong progression-free survival.…
Author: | Viktoria Fuhr, Shanice Heidenreich, Mugdha Srivastava, Angela Riedel, Johannes Düll, Elena Gerhard-Hartmann, Andreas Rosenwald, Hilka Rauert-Wunderlich |
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URN: | urn:nbn:de:bvb:20-opus-300817 |
Document Type: | Journal article |
Faculties: | Medizinische Fakultät / Pathologisches Institut |
Medizinische Fakultät / Medizinische Klinik und Poliklinik II | |
Language: | English |
Parent Title (English): | Cell Death Discovery |
ISSN: | 2058-7716 |
Year of Completion: | 2022 |
Volume: | 8 |
Article Number: | 505 |
Source: | Cell Death Discovery (2022) 8:505. https://doi.org/10.1038/s41420-022-01289-7 |
DOI: | https://doi.org/10.1038/s41420-022-01289-7 |
Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Tag: | cancer metabolism; cell death; target validation; targeted therapies |
Release Date: | 2023/05/02 |
Open-Access-Publikationsfonds / Förderzeitraum 2022 | |
Licence (German): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |