Biomol Ther  
Differential Gene Expression Common to Acquired and Intrinsic Resistance to BRAF Inhibitor Revealed by RNA-Seq Analysis
Jun-Ho Ahn1,†, Sung-Hee Hwang2,†, Hyun-Soo Cho3,4 and Michael Lee2,*
1System Toxicology Research Center, Korea Institute of Toxicology, Daejeon 34114,
2Division of Life Sciences, College of Life Sciences and Bioengineering, Incheon National University, Incheon 22012,
3Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141,
4Department of Functional Genomics, Korea University of Science and Technology, Daejeon 34113, Republic of Korea
Tel: +82-32-835-8247, Fax: +82-32-835-0763
The first two authors contributed equally to this work.
Received: July 17, 2018; Revised: August 14, 2018; Accepted: August 16, 2018; Published online: October 4, 2018.
© The Korean Society of Applied Pharmacology. All rights reserved.

Melanoma cells have been shown to respond to BRAF inhibitors; however, intrinsic and acquired resistance limits their clinical application. In this study, we performed RNA-Seq analysis with BRAF inhibitor-sensitive (A375P) and -resistant (A375P/Mdr with acquired resistance and SK-MEL-2 with intrinsic resistance) melanoma cell lines, to reveal the genes and pathways potentially involved in intrinsic and acquired resistance to BRAF inhibitors. A total of 546 differentially expressed genes (DEGs), including 239 up-regulated and 307 down-regulated genes, were identified in both intrinsic and acquired resistant cells. Gene ontology (GO) analysis revealed that the top 10 biological processes associated with these genes included angiogenesis, immune response, cell adhesion, antigen processing and presentation, extracellular matrix organization, osteoblast differentiation, collagen catabolic process, viral entry into host cell, cell migration, and positive regulation of protein kinase B signaling. In addition, using the PANTHER GO classification system, we showed that the highest enriched GOs targeted by the 546 DEGs were responses to cellular processes (ontology: biological process), binding (ontology: molecular function), and cell subcellular localization (ontology: cellular component). Ingenuity pathway analysis (IPA) network analysis showed a network that was common to two BRAF inhibitor-resistant cells. Taken together, the present study may provide a useful platform to further reveal biological processes associated with BRAF inhibitor resistance, and present areas for therapeutic tool development to overcome BRAF inhibitor resistance.
Keywords: BRAF inhibitor, Drug resistance, Melanoma, RNA-Seq analysis

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