Molecule Information

General Information of the Molecule (ID: Mol01857)

• Name: C-C motif chemokine receptor 4 (CCR4) ,Homo sapiens
• Synonyms: CCR4; CMKBR4
• Molecule Type: Protein
• Gene Name: CCR4
• Gene ID: 1233
• Location: chr3:32,951,644-32,956,349[+]
• Sequence:
  MNPTDIADTTLDESIYSNYYLYESIPKPCTKEGIKAFGELFLPPLYSLVFVFGLLGNSVV
  VLVLFKYKRLRSMTDVYLLNLAISDLLFVFSLPFWGYYAADQWVFGLGLCKMISWMYLVG
  FYSGIFFVMLMSIDRYLAIVHAVFSLRARTLTYGVITSLATWSVAVFASLPGFLFSTCYT
  ERNHTYCKTKYSLNSTTWKVLSSLEINILGLVIPLGIMLFCYSMIIRTLQHCKNEKKNKA
  VKMIFAVVVLFLGFWTPYNIVLFLETLVELEVLQDCTFERYLDYAIQATETLAFVHCCLN
  PIIYFFLGEKFRKYILQLFKTCRGLFVLCQYCGLLQIYSADTPSSSYTQSTMDHDLHDAL
• Function: High affinity receptor for the C-C type chemokines CCL17/TARC, CCL22/MDC and CKLF isoform 1/CKLF1. The activity of this receptor is mediated by G(i) proteins which activate a phosphatidylinositol-calcium second messenger system. Can function as a chemoattractant homing receptor on circulating memory lymphocytes and as a coreceptor for some primary HIV-2 isolates. In the CNS, could mediate hippocampal-neuron survival.
• Uniprot ID: CCR4_HUMAN
• Ensembl ID: ENSG00000183813
• HGNC ID: HGNC:1605

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Mogamulizumab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Cutaneous T-cell lymphomas [1]

• 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.

References

• Ref 1: 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