Genomics & Informatics

Korea Genome Organization (한국유전체학회)
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Elucidating molecular mechanisms of acquired resistance to BRAF inhibitors in melanoma using a microfluidic device and deep sequencing

  • Han, Jiyeon (Department of Bio-information Science, Ewha Womans University) ;
  • Jung, Yeonjoo (Ewha Research Center for Systems Biology (ERCSB), Ewha Womans University) ;
  • Jun, Yukyung (Center for Supercomputing Application, Division of National Supercomputing, Korea Institute of Science and Technology Information) ;
  • Park, Sungsu (School of Mechanical Engineering, Sungkyunkwan University) ;
  • Lee, Sanghyuk (Department of Bio-information Science, Ewha Womans University)
  • Received : 2020.12.11
  • Accepted : 2021.01.15
  • Published : 2021.03.31
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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.

Keywords

Acknowledgement

A portion of the data used for this study were obtained from the Genome-InfraNet (IDs: 10050154, 1711072542, 1711027157, and 1711038047) of the Korea Bioinformation Center.

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