Drug Information

Drug (ID: DG01436) and It's Reported Resistant Information

• Name: Tagraxofusp
• Indication:
  In total 2 Indication(s)
  Acute myeloid leukaemia [ICD-11: 2A60]; Approved; [1]
  Blastic plasmacytoid dendritic cell neoplasm [ICD-11: 2A60]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Acute myeloid leukemia [ICD-11: 2A60]; [1]
• Target: Interleukin 3 receptor alpha (IL3RA); IL3RA_HUMAN; [1]
• TTD Drug ID: D0R7NI

Type(s) of Resistant Mechanism of This Drug

  EADR: Epigenetic Alteration of DNA, RNA or Protein

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Acute myeloid leukemia [ICD-11: 2A60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Diphthamide biosynthesis 1 (DPH1) [1]

• Molecule Alteration: Expression; Down-regulation
• Resistant Disease: Blastic plasmacytoid dendritic cell neoplasm [ICD-11: 2A60.5]
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vivo Model: NSG mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Loss of DPH1 is sufficient to confer relative tagraxofusp resistance in AML cells. CpGs further upstream, between -300 and -80 bases from the transcription start site (TSS), showed no significant change in methylation, suggesting that increased DPH1-promoter methylation associated with tagraxofusp resistance may confer a specific advantage. Given this finding, we hypothesized that azacitidine, a DNA methyltransferase inhibitor or DNA hypomethylating agent (HMA) might reverse resistance-associated DPH1 hypermethylation and restore DPH1 expression.

References

• Ref 1: DNA methyltransferase inhibition overcomes diphthamide pathway deficiencies underlying CD123-targeted treatment resistance .J Clin Invest. 2019 Nov 1;129(11):5005-5019. doi: 10.1172/JCI128571. 10.1172/JCI128571