Disease Information

General Information of the Disease (ID: DIS00059)

• Name: Cutaneous T-cell lymphoma
• ICD: ICD-11: 2B00

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Bortezomib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-125b-5p [1]

• Resistant Disease: Cutaneous T-cell lymphomas [ICD-11: 2B00.0]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Bortezomib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: MyLa2000 cells; Skin; Homo sapiens (Human); CVCL_8328
• In Vitro Model: SeAx cells; Skin; Homo sapiens (Human); CVCL_5363
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Bortezomib repressed cMyc and simultaneously induced miR-125b-5p that exerted a cytoprotective effect through the downmodulation of MAD4. miR-125b-5p can regulates tumor growth in vivo,and increases cellular resistance to proteasome inhibitors via modulation of MAD4.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Max dimerization protein 4 (MXD4) [1]

• Resistant Disease: Cutaneous T-cell lymphomas [ICD-11: 2B00.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Bortezomib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: MyLa2000 cells; Skin; Homo sapiens (Human); CVCL_8328
• In Vitro Model: SeAx cells; Skin; Homo sapiens (Human); CVCL_5363
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Bortezomib repressed cMyc and simultaneously induced miR-125b-5p that exerted a cytoprotective effect through the downmodulation of MAD4. miR-125b-5p can regulates tumor growth in vivo,and increases cellular resistance to proteasome inhibitors via modulation of MAD4.

Mogamulizumab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: C-C motif chemokine receptor 4 (CCR4) [2]

• Resistant Disease: Cutaneous T-cell lymphomas [ICD-11: 2B00.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Mogamulizumab
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Mechanism Description: We identified 17 patients with mycosis fungoides or Sezary syndrome who either were intrinsically resistant or acquired resistance to mogamulizumab. Low expression of CCR4 by immunohistochemistry or flow cytometry was found in 65% of patients. Novel emergent CCR4 mutations targeting the N-terminal and transmembrane domains were found in 3 patients after disease progression. Emerging CCR4 copy number loss was detected in 2 patients with CCR4 mutations. Acquisition of CCR4 genomic alterations corresponded with loss of CCR4 antigen expression. We also report on outcomes of three cutaneous T-cell lymphoma patients with gain-of-function CCR4 mutations treated with mogamulizumab. Our study indicates that resistance to mogamulizumab in CTCL frequently involves loss of CCR4 expression and emergence of CCR4 genomic alterations.

References

• Ref 1: cMyc/miR-125b-5p signalling determines sensitivity to bortezomib in preclinical model of cutaneous T-cell lymphomas. PLoS One. 2013;8(3):e59390. doi: 10.1371/journal.pone.0059390. Epub 2013 Mar 19.
• Ref 2: Resistance to mogamulizumab is associated with loss of CCR4 in Cutaneous T-cell Lymphoma .Blood. 2022 Apr 18:blood.2021014468. doi: 10.1182/blood.2021014468. Online ahead of print. 10.1182/blood.2021014468