Drug Information
Drug (ID: DG01751) and It's Reported Resistant Information
| Name |
Dasatinib/Trametinib
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| Synonyms |
Dasatinib/Trametinib
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| Target | . | NOUNIPROTAC | [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
Thyroid cancer [ICD-11: 2D10]
| Drug Sensitivity Data Categorized by Their Corresponding Mechanisms | ||||
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Unusual Activation of Pro-survival Pathway (UAPP)
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| Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) | [1] | |||
| Molecule Alteration | Missense mutation | p.V600E (c.1799T>A) |
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| Sensitive Disease | Thyroid gland cancer [ICD-11: 2D10.0] | |||
| Experimental Note | Revealed Based on the Cell Line Data | |||
| Cell Pathway Regulation | BRAF/MEK/MAPK signaling pathway | Inhibition | hsa04010 | |
| In Vitro Model | A375 cells | Skin | Homo sapiens (Human) | CVCL_0132 |
| BCPAP cells | Thyroid | Homo sapiens (Human) | CVCL_0153 | |
| SW1736 cells | Thyroid | Homo sapiens (Human) | CVCL_3883 | |
| C643 cells | Thyroid gland | Homo sapiens (Human) | CVCL_5969 | |
| CAL62 cells | Thyroid gland | Homo sapiens (Human) | CVCL_1112 | |
| In Vivo Model | Athymic nude mouse PDX xenografts model | Mus musculus | ||
| Experiment for Molecule Alteration |
Immunoblotting assay; Immunoprecipitation assy | |||
| Experiment for Drug Resistance |
SRB staining assay; Promega assay | |||
| Mechanism Description | Activation of the Mitogen Activated Protein (MAP) Kinase pathway was increased in all four of the dasatinib-resistant cell lines, likely due to B-Raf and c-Raf dimerization. Furthermore, MAP2K1/MAP2K2 (MEK1/2) inhibition restored sensitivity in all four of the dasatinib-resistant cell lines, and overcome acquired resistance to dasatinib in the RAS-mutant Cal62 cell line, in vivo. Together, these studies demonstrate that acquisition of the c-Src gatekeeper mutation and MAP Kinase pathway signaling play important roles in promoting resistance to the Src inhibitor, dasatinib. | |||
References
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