Characterization of resistance to a recombinant hexameric Fas-ligand (APO010) in human cancer cell lines
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Characterization of resistance to a recombinant hexameric Fas-ligand (APO010) in human cancer cell lines. / Jandu, Haatisha; Nielsen, Annette; Brunner, Nils; Hansen, Anker; Knudsen, Steen; Stenvang, Jan; Jensen, Peter B.
In: Experimental Hematology, Vol. 87, 2020, p. 33-41.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Characterization of resistance to a recombinant hexameric Fas-ligand (APO010) in human cancer cell lines
AU - Jandu, Haatisha
AU - Nielsen, Annette
AU - Brunner, Nils
AU - Hansen, Anker
AU - Knudsen, Steen
AU - Stenvang, Jan
AU - Jensen, Peter B.
PY - 2020
Y1 - 2020
N2 - Multiple myeloma remains a hard-to-treat cancer as all patients eventually progress because of drug resistance. Thus, there is a need for novel and non-cross-resistant treatment options, and we aimed to address this issue by introducing a new immunooncology drug (APO010) in multiple myeloma treatment. APO010 is a hexameric Fas-ligand that mimics cytotoxic T-lymphocyte signaling through the Fas-receptor to induce apoptosis. APO010 is currently in clinical trials with multiple myeloma patients. Thus, an understanding of the mechanisms contributing to resistance to APO010 will be essential for future clinical studies with APO010, and it might be possible to develop strategies to circumvent this resistance. We developed APO010-resistant variants of human multiple myeloma cell lines (LP1, MOLP-8, and KMS-12-BM) and a human Burkitt's lymphoma cell line (Raji) by exposing the cells to gradually increasing concentrations of APO010 over a period of 6-12 months. The resistant cell lines were characterized on the basis of immunocytochemistry, Fas-receptor protein expression, mRNA expression analysis, and pathway analysis. APO010-resistant cell lines exhibited a 4- to 520-fold increase in resistance to APO010 and still remained sensitive to other chemotherapeutics. Downregulation of the Fas-receptor protein expression was observed in all resistant cell lines. mRNA expression analysis of the resistant versus parental cell lines confirmed a significant alteration in FAS expression between sensitive and resistant cell lines (p = 0.03), while pathway analysis revealed alterations in mRNA signaling pathways of Fas. On the basis of the pre-clinical data obtained, it can be concluded that downregulation of Fas-receptor can mediate resistance to APO010. (C) 2020 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.
AB - Multiple myeloma remains a hard-to-treat cancer as all patients eventually progress because of drug resistance. Thus, there is a need for novel and non-cross-resistant treatment options, and we aimed to address this issue by introducing a new immunooncology drug (APO010) in multiple myeloma treatment. APO010 is a hexameric Fas-ligand that mimics cytotoxic T-lymphocyte signaling through the Fas-receptor to induce apoptosis. APO010 is currently in clinical trials with multiple myeloma patients. Thus, an understanding of the mechanisms contributing to resistance to APO010 will be essential for future clinical studies with APO010, and it might be possible to develop strategies to circumvent this resistance. We developed APO010-resistant variants of human multiple myeloma cell lines (LP1, MOLP-8, and KMS-12-BM) and a human Burkitt's lymphoma cell line (Raji) by exposing the cells to gradually increasing concentrations of APO010 over a period of 6-12 months. The resistant cell lines were characterized on the basis of immunocytochemistry, Fas-receptor protein expression, mRNA expression analysis, and pathway analysis. APO010-resistant cell lines exhibited a 4- to 520-fold increase in resistance to APO010 and still remained sensitive to other chemotherapeutics. Downregulation of the Fas-receptor protein expression was observed in all resistant cell lines. mRNA expression analysis of the resistant versus parental cell lines confirmed a significant alteration in FAS expression between sensitive and resistant cell lines (p = 0.03), while pathway analysis revealed alterations in mRNA signaling pathways of Fas. On the basis of the pre-clinical data obtained, it can be concluded that downregulation of Fas-receptor can mediate resistance to APO010. (C) 2020 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.
KW - MULTIPLE-MYELOMA
KW - ANTI-FAS
KW - APOPTOSIS
KW - RECEPTOR
KW - IMMUNOTHERAPY
KW - SENSITIVITY
KW - EXPRESSION
KW - INHIBITORS
KW - IMPACT
U2 - 10.1016/j.exphem.2020.06.005
DO - 10.1016/j.exphem.2020.06.005
M3 - Journal article
C2 - 32619459
VL - 87
SP - 33
EP - 41
JO - Experimental Hematology
JF - Experimental Hematology
SN - 0301-472X
ER -
ID: 248894013