%0 Journal Article %1 fuhr2022oxphospotential %A Fuhr, Viktoria %A Heidenreich, Shanice %A Srivastava, Mugdha %A Riedel, Angela %A Düll, Johannes %A Gerhard-Hartmann, Elena %A Rosenwald, Andreas %A Rauert-Wunderlich, Hilka %D 2022 %J Cell Death Discovery %K myown %N 1 %P 505 %R https://doi.org/10.1038/s41420-022-01289-7 %T CD52 and OXPHOS—potential targets in ibrutinib-treated mantle cell lymphoma %U https://doi.org/10.1038/s41420-022-01289-7 %V 8 %X 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 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.

@article{fuhr2022oxphospotential, abstract = {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 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.}, added-at = {2023-02-15T21:02:54.000+0100}, author = {Fuhr, Viktoria and Heidenreich, Shanice and Srivastava, Mugdha and Riedel, Angela and Düll, Johannes and Gerhard-Hartmann, Elena and Rosenwald, Andreas and Rauert-Wunderlich, Hilka}, biburl = {https://www.bibsonomy.org/bibtex/23b77df0754c6a4ec2513c3b8113a683f/cusysmed}, day = 31, doi = {https://doi.org/10.1038/s41420-022-01289-7}, interhash = {fdd4170fee66941ddb9b933158ebff75}, intrahash = {3b77df0754c6a4ec2513c3b8113a683f}, journal = {Cell Death Discovery }, keywords = {myown}, month = dec, number = 1, pages = 505, timestamp = {2024-04-16T15:01:42.000+0200}, title = {CD52 and OXPHOS—potential targets in ibrutinib-treated mantle cell lymphoma}, url = {https://doi.org/10.1038/s41420-022-01289-7}, volume = {8 }, year = 2022 }