4.8 Article

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

期刊

JOURNAL OF CLINICAL INVESTIGATION
卷 129, 期 11, 页码 5005-5019

出版社

AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI128571

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资金

  1. Ludwig Cancer Research
  2. National Cancer Institute [CA066996, CA225191-01]
  3. Stand Up to Cancer [D2015-037]
  4. The V Foundation (TVF) SU2-CTVF Convergence Scholar Awards [D2015-037]
  5. Ramon y Cajal Programme, Ministerio de Economia y Competitividad [RYC-2015-18357]
  6. Gerstner Family Foundation
  7. Stemline Therapeutics
  8. Doris Duke Charitable Foundation (DDCF) [2017065]

向作者/读者索取更多资源

The interleukin-3 receptor alpha 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 00123 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 CD123, 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.

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