Abstract
BRAF mutations occur in approximately 50% of melanoma patients. The mutated BRAF kinase continuously activates the mitogen-activated protein kinase (MAPK) pathway to promote cell growth and proliferation. Vemurafenib as a specific BRAF inhibitor can significantly prolong progression-free survival in melanoma patients. However, most patients developed resistance to Vemurafenib after 6 months. The mechanism of drug resistance is not yet fully understood. In this study, we found that proteins secreted by drug-resistant cells protect sensitive cells from Vemurafenib. By RNA-seq, we compared differentially expressed genes between resistant and sensitive cells. We demonstrated that drug-resistant cells secrete more IL-6 protein than sensitive cells. For the first time, we found that IL-6 expressed by drug-resistant cells consists of the following transcripts: IL6-201, IL6-202 and IL6-205. We confirmed that it is the IL6-202 and IL6-205 transcripts that confer drug resistance to Vemurafenib by reactivating the MAPK pathway while IL6-201 is not responsible for the resistance in A375 melanoma cells. Neutralizing IL-6 significantly increased the sensitivity of drug-resistant cells to Vemurafenib. Overall, these results reveal a new mechanism of drug resistance in melanoma.
Keywords:
BRAF; IL6-202; IL6-205; Melanoma; Vemurafenib.
Copyright © 2020 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibodies / pharmacology
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Antineoplastic Agents / pharmacology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Resistance, Neoplasm / drug effects*
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Drug Resistance, Neoplasm / genetics
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Gene Expression Regulation, Neoplastic*
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Humans
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Interleukin-6 / antagonists & inhibitors
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Interleukin-6 / genetics*
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Interleukin-6 / metabolism
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Melanocytes / drug effects*
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Melanocytes / enzymology
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Melanocytes / pathology
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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Mutation
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins B-raf / antagonists & inhibitors
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Proto-Oncogene Proteins B-raf / genetics*
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Proto-Oncogene Proteins B-raf / metabolism
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RNA, Messenger / genetics*
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RNA, Messenger / metabolism
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / metabolism
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Signal Transduction
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Vemurafenib / pharmacology
Substances
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Antibodies
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Antineoplastic Agents
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IL6 protein, human
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Interleukin-6
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Protein Isoforms
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Protein Kinase Inhibitors
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RNA, Messenger
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STAT3 Transcription Factor
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Stat3 protein, mouse
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Vemurafenib
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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MAPK3 protein, human
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Mapk1 protein, mouse
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3