Open AccessAnti-CD37 radioimmunotherapy with 177Lu-NNV003 synergizes with the PARP inhibitor olaparib in treatment of non-Hodgkin’s lymphoma in vitro
Author(s) -
Marion Masitsa Malenge,
Astri Fjelde Maaland,
Ada H. V. Repetto-Llamazares,
Brian Middleton,
Marcel Nijland,
Lydia Visser,
Sebastian Patzke,
Helèn Heyerdahl,
Arne Kolstad,
Trond Stokke,
Anne Hansen Ree,
Jostein Dahle
Publication year - 2022
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0267543
Subject(s) - radioimmunotherapy , olaparib , parp inhibitor , cancer research , lymphoma , in vitro , medicine , poly adp ribose polymerase , chemistry , immunology , monoclonal antibody , antibody , biochemistry , enzyme , polymerase
Background and purpose PARP inhibitors have been shown to increase the efficacy of radiotherapy in preclinical models. Radioimmunotherapy results in selective radiation cytotoxicity of targeted tumour cells. Here we investigate the combined effect of anti-CD37 β-emitting 177 Lu-NNV003 radioimmunotherapy and the PARP inhibitor olaparib, and gene expression profiles in CD37 positive non-Hodgkin’s lymphoma cell lines. Materials and methods The combined effect of 177 Lu-NNV003 and olaparib was studied in seven cell lines using a fixed-ratio ray design, and combination index was calculated for each combination concentration. mRNA was extracted before and after treatment with the drug combination. After RNA-sequencing, hierarchical clustering was performed on basal gene expression profiles and on differentially expressed genes after combination treatment from baseline. Functional gene annotation analysis of significant differentially expressed genes after combination treatment was performed to identify enriched biological processes. Results The combination of olaparib and 177 Lu-NNV003 was synergistic in four of seven cell lines, antagonistic in one and both synergistic and antagonistic (conditionally synergistic) in two, depending on the concentration ratio between olaparib and 177 Lu-NNV003. Cells treated with the combination significantly overexpressed genes in the TP53 signalling pathway. However, cluster analysis did not identify gene clusters that correlate with the sensitivity of cells to single agent or combination treatment. Conclusion The cytotoxic effect of the combination of the PARP inhibitor olaparib and the β-emitting radioimmunoconjugate 177 Lu-NNV003 was synergistic in the majority of tested lymphoma cell lines.