Drug Information

Drug (ID: DG00463) and It's Reported Resistant Information

Name	Anastrazola/Goserelin
Drug Resistance Disease(s)	Disease(s) with Clinically Reported Resistance for This Drug (1 diseases) Breast cancer [ICD-11: 2C60] [1]

Type(s) of Resistant Mechanism of This Drug

UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

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

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Breast cancer [ICD-11: 2C60]

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Drug Resistance Data Categorized by Their Corresponding Mechanisms
Unusual Activation of Pro-survival Pathway (UAPP)		Click to Show/Hide
Key Molecule: Estrogen receptor alpha (ESR1)			[1]
Molecule Alteration	Missense mutation	p.D538G	Molecule Info
Resistant Disease	Breast cancer [ICD-11: 2C60.3]		Disease Info
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.