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Elucidating molecular mechanisms of acquired resistance to BRAF inhibitors in melanoma using a microfluidic device and deep sequencing

Title
Elucidating molecular mechanisms of acquired resistance to BRAF inhibitors in melanoma using a microfluidic device and deep sequencing
Authors
Han J.Jung Y.Jun Y.Park S.Lee S.
Ewha Authors
이상혁정연주
SCOPUS Author ID
이상혁scopusscopus; 정연주scopus
Issue Date
2021
Journal Title
Genomics and Informatics
ISSN
2234-0742JCR Link
Citation
Genomics and Informatics vol. 19, no. 1
Keywords
Cancer drug resistanceMelanomaMicrofluidic deviceRNA sequencingTargeted therapyWhole exome sequencing
Publisher
Korea Genome Organization
Indexed
SCOPUS scopus
Document Type
Article
Abstract
BRAF inhibitors (e.g., vemurafenib) are widely used to treat metastatic melanoma with the BRAF V600E mutation. The initial response is often dramatic, but treatment resistance leads to disease progression in the majority of cases. Although secondary mutations in the mitogen-activated protein kinase signaling pathway are known to be responsible for this phenomenon, the molecular mechanisms governing acquired resistance are not known in more than half of patients. Here we report a genome- and transcriptome-wide study investigating the molecular mechanisms of acquired resistance to BRAF inhibitors. A microfluidic chip with a concentration gradient of vemurafenib was utilized to rapidly obtain therapy-resistant clones from two melanoma cell lines with the BRAF V600E mutation (A375 and SK-MEL-28). Exome and transcriptome data were produced from 13 resistant clones and analyzed to identify secondary mutations and gene expression changes. Various mechanisms, including phenotype switching and metabolic reprogramming, have been determined to contribute to resistance development differently for each clone. The roles of microphthalmia-associated transcription factor, the master transcription factor in melanocyte differentiation/dedifferentiation, were highlighted in terms of phenotype switching. Our study provides an omics-based comprehensive overview of the molecular mechanisms governing acquired resistance to BRAF inhibitor therapy. © 2021, Korea Genome Organization.
DOI
10.5808/gi.20074
Appears in Collections:
자연과학대학 > 생명과학전공 > Journal papers
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