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) 4 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]
• Resistant Drug: Bortezomib
• Molecule Alteration: Expression; Up-regulation
• 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.

Key Molecule: hsa-miR-122 [2]

• Resistant Disease: Cutaneous T-cell lymphomas [ICD-11: 2B00.0]
• Resistant Drug: Bortezomib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: p53/AKT Signalling; Regulation; N.A.
• In Vitro Model: MyLa2000 cells; Skin; Homo sapiens (Human); CVCL_8328
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Flow cytometry assays
• Mechanism Description: We found that miR-122 was significantly increased in the apoptotic cells. miR-122 up-regulation was not specific for GSI-1 but was also seen during apoptosis induced by chemotherapies including doxorubicin and proteasome blockers (bortezomib, MG132). miR-122 was not expressed in quiescent T-cells, but was detectable in CTCL: in lesional skin in mycosis fungoides and in Sezary cells purified from peripheral blood. In situ hybridization results showed that miR-122 was expressed in the malignant T-cell infiltrate and increased in the advanced stage mycosis fungoides. Surprisingly, miR-122 overexpression decreased the sensitivity to the chemotherapy-induced apoptosis via a signaling circuit involving the activation of Akt and inhibition of p53. We have also shown that induction of miR-122 occurred via p53 and that p53 post-transcriptionally up-regulated miR-122. miR-122 is thus an amplifier of the antiapoptotic Akt/p53 circuit and it is conceivable that a pharmacological intervention in this pathway may provide basis for novel therapies for CTCL.

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]
• Resistant Drug: Bortezomib
• Molecule Alteration: Expression; Down-regulation
• 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 blot 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.

Cantharidin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Interleukin-2 receptor subunit alpha (IL-2Ralpha) [3]

• Sensitive Disease: Cutaneous T-cell lymphomas [ICD-11: 2B00.0]
• Sensitive Drug: Cantharidin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: JAK-STAT signaling pathway; Activation; hsa04630
• Cell Pathway Regulation: AKT/mTOR signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vitro Model: H9SR cells; embryonic stem cell; Homo sapiens (Human); N.A.
• In Vitro Model: HHSR cells; embryonic stem cell; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay; Immunohistochemistry
• Experiment for Drug Resistance: Flow cytometric assay
• Mechanism Description: Our findings highlight that attenuated ROS accelerates IL-2R translation and therefore brings about aberrant expression of IL-2R protein, leading to overactivation of JAK/STAT, AKT/mTOR and MAPK signaling events, which explains SAHA resistance to CTCL cells. Moreover, cantharidin could overcome SAHA resistance to CTCL by blocking IL-2R-related signaling via ROS dependent manner.

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) [4]

• Resistant Disease: Cutaneous T-cell lymphomas [ICD-11: 2B00.0]
• Resistant Drug: Mogamulizumab
• Molecule Alteration: Expression; Down-regulation
• 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.

Vorinostat

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Interleukin-2 receptor subunit alpha (IL-2Ralpha) [3]

• Resistant Disease: Cutaneous T-cell lymphomas [ICD-11: 2B00.0]
• Resistant Drug: Vorinostat
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: JAK-STAT signaling pathway; Activation; hsa04630
• Cell Pathway Regulation: AKT/mTOR signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: MAPK signaling pathway; Activation; hsa04010
• In Vitro Model: H9SR cells; embryonic stem cell; Homo sapiens (Human); N.A.
• In Vitro Model: HHSR cells; embryonic stem cell; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay; Immunohistochemistry
• Experiment for Drug Resistance: Flow cytometric assay
• Mechanism Description: Our findings highlight that attenuated ROS accelerates IL-2R translation and therefore brings about aberrant expression of IL-2R protein, leading to overactivation of JAK/STAT, AKT/mTOR and MAPK signaling events, which explains SAHA resistance to CTCL cells. Moreover, cantharidin could overcome SAHA resistance to CTCL by blocking IL-2R-related signaling via ROS dependent manner.

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: CEP-28122, a highly potent and selective orally active inhibitor of anaplastic lymphoma kinase with antitumor activity in experimental models of human cancersMol Cancer Ther. 2012 Mar;11(3):670-9. doi: 10.1158/1535-7163.MCT-11-0776. Epub 2011 Dec 27.
• Ref 3: Cantharidin overcomes IL-2Ralpha signaling-mediated vorinostat resistance in cutaneous T-cell lymphoma through reactive oxygen species. J Immunother Cancer. 2024 Jul 14;12(7):e009099.
• Ref 4: 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