Drug Information

Drug (ID: DG00475) and It's Reported Resistant Information

• Name: Tamoxifen/Goserelin
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (2 diseases)
  Breast cancer [ICD-11: 2C60]; [1]
  COVID-19 [ICD-11: 1D92]; [2]

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

Drug Resistance Data Categorized by Their Corresponding Diseases

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

Breast cancer [ICD-11: 2C60]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Estrogen receptor alpha (ESR1) [1]

• Molecule Alteration: Missense mutation; p.D538G
• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Deep sequencing assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: We report here on a novel mutation of ERalpha, in which an A to G substitution at position 1,613 resulted in substitution of aspartic acid at position 538 to glycine (D538G). The mutation was identified in liver metastases obtained from patients who developed endocrine resistance, but not in samples of primary tumors obtained prior to commencing endocrine treatment. Structural modeling indicates that D538G substitution creates a conformational change that disrupts the interaction between the receptor and either estrogen or tamoxifen, but mimics the conformation of the activated receptor. Studies in cell lines confirmed ligand-independent, constitutive activity of the mutated receptor. Taken together, these data indicate the mutation D538G as a novel mechanism conferring acquired endocrine resistance.

References

• Ref 1: D538G mutation in estrogen receptor-Alpha: A novel mechanism for acquired endocrine resistance in breast cancer. Cancer Res. 2013 Dec 1;73(23):6856-64. doi: 10.1158/0008-5472.CAN-13-1197. Epub 2013 Nov 11.
• Ref 2: Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies Nat Med. 2021 Apr;27(4):717-726. doi: 10.1038/s41591-021-01294-w. Epub 2021 Mar 4.