DNA methyltransferase inhibition overcomes diphthamide pathway deficiencies underlying CD123-targeted treatment resistance

The interleukin-3 receptor α subunit, CD123, is expressed in many hematologic malignancies including acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Tagraxofusp (SL-401) is a CD123-targeted therapy consisting of interleukin-3 fused to a truncated diphtheria tox...

Ausführliche Beschreibung

Gespeichert in:

Bibliographische Detailangaben
Veröffentlicht in:	The Journal of clinical investigation Jg. 129; H. 11; S. 5005 - 5019
Hauptverfasser:	Togami, Katsuhiro, Pastika, Timothy, Stephansky, Jason, Ghandi, Mahmoud, Christie, Amanda L., Jones, Kristen L., Johnson, Carl A., Lindsay, Ross W., Brooks, Christopher L., Letai, Anthony, Craig, Jeffrey W., Pozdnyakova, Olga, Weinstock, David M., Montero, Joan, Aster, Jon C., Johannessen, Cory M., Lane, Andrew A.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States American Society for Clinical Investigation 01.11.2019
Schlagworte:	Acute myelocytic leukemia Acute myeloid leukemia ADP-ribosylation Animals Antineoplastic Combined Chemotherapy Protocols - pharmacology Apoptosis Azacitidine - pharmacology Biomarkers Biomedical research Blinatumomab Blood cancer Bone marrow Cancer Cancer therapies CD123 antigen Cell Line, Tumor Chemotherapy CpG islands Cytokines Cytotoxicity Dendritic cells Dendritic Cells - metabolism Dendritic Cells - pathology Deoxyribonucleic acid Diphtheria Diphtheria toxin DNA DNA Methylation DNA methyltransferase Drug Delivery Systems Drug dosages Enzymes Female Genomes Hematologic Neoplasms - drug therapy Hematologic Neoplasms - metabolism Hematologic Neoplasms - pathology Humans Inotuzumab ozogamicin Interleukin 3 Interleukin-3 Receptor alpha Subunit - metabolism Interleukins Leukemia Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - metabolism Leukemia, Myeloid, Acute - pathology Male Methylation Mice Mice, Nude Minor Histocompatibility Antigens - metabolism Mitochondria Myeloid leukemia Neoplasm Proteins - metabolism Patients Recombinant Fusion Proteins - pharmacology Ribosylation Scientific equipment industry Tagraxofusp Transferases Treatment resistance Tumor Suppressor Proteins - metabolism Tumors Xenograft Model Antitumor Assays Xenografts United States Massachusetts United States > US Oncology Hematology Molecular biology Leukemias Toxins/drugs/xenobiotics
ISSN:	0021-9738, 1558-8238, 1558-8238
Online-Zugang:	Volltext
Tags:	Tag hinzufügen Keine Tags, Fügen Sie den ersten Tag hinzu!

Beschreibung
Zusammenfassung:	The interleukin-3 receptor α subunit, CD123, is expressed in many hematologic malignancies including acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Tagraxofusp (SL-401) is a CD123-targeted therapy consisting of interleukin-3 fused to a truncated diphtheria toxin payload. Factors influencing response to tagraxofusp other than CD123 expression are largely unknown. We interrogated tagraxofusp resistance in patients and experimental models and found that it was not associated with CD123 loss. Rather, resistant AML and BPDCN cells frequently acquired deficiencies in the diphthamide synthesis pathway, impairing tagraxofusp's ability to ADP-ribosylate cellular targets. Expression of DPH1, encoding a diphthamide pathway enzyme, was reduced by DNA CpG methylation in resistant cells. Treatment with the DNA methyltransferase inhibitor azacitidine restored DPH1 expression and tagraxofusp sensitivity. We also developed a drug-dependent ADP-ribosylation assay in primary cells that correlated with tagraxofusp activity and may represent an additional novel biomarker. As predicted by these results and our observation that resistance also increased mitochondrial apoptotic priming, we found that the combination of tagraxofusp and azacitidine was effective in patient-derived xenografts treated in vivo. These data have important implications for clinical use of tagraxofusp and led to a phase 1 study combining tagraxofusp and azacitidine in myeloid malignancies.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Authorship note: KT, TP, and JS are co–first authors.
ISSN:	0021-9738 1558-8238 1558-8238
DOI:	10.1172/JCI128571