Combinatorial drug screening and molecular profiling reveal diverse mechanisms of intrinsic and adaptive resistance to BRAF inhibition in V600E BRAF mutant melanomas
| Autor: | Devin G. Roller, Daniel Gioeli, Aaron J. Mackey, Brian J. Capaldo, Emanuel F. Petricoin, Stefan Bekiranov, Mark R. Conaway, Michael J. Weber |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
therapeutic resistance Proto-Oncogene Proteins B-raf Cell signaling Indoles MAP Kinase Signaling System Drug Evaluation Preclinical Mice Nude Drug resistance Mice SCID Lapatinib Bioinformatics Receptor tyrosine kinase BRAF 03 medical and health sciences Mice Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols medicine melanoma cell signaling Animals Humans Protein Kinase Inhibitors Sulfonamides biology business.industry Melanoma medicine.disease Molecular medicine 3. Good health 030104 developmental biology Oncology Drug Resistance Neoplasm Cancer research biology.protein Quinazolines business human activities V600E MAP Kinase medicine.drug Research Paper |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Devin G. Roller 1 , Brian Capaldo 2 , Stefan Bekiranov 2 , Aaron J. Mackey 3 , Mark R. Conaway 3 , Emanuel F. Petricoin 4 , Daniel Gioeli 1 , Michael J. Weber 1 1 Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, 22908 USA 2 Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, 22908 USA 3 Department of Public Health Sciences, University of Virginia, Charlottesville, VA, 22908 USA 4 Center for Applied Proteomics and Molecular Medicine, School of Systems Biology, College of Science, George Mason University, Manassas, VA 20110, USA Correspondence to: Michael J. Weber, e-mail: mjw@virginia.edu Keywords: melanoma, therapeutic resistance, cell signaling, BRAF, MAP Kinase Received: August 20, 2015 Accepted: November 21, 2015 Published: December 10, 2015 ABSTRACT Over half of BRAFV600E melanomas display intrinsic resistance to BRAF inhibitors, in part due to adaptive signaling responses. In this communication we ask whether BRAFV600E melanomas share common adaptive responses to BRAF inhibition that can provide clinically relevant targets for drug combinations. We screened a panel of 12 treatment-naive BRAFV600E melanoma cell lines with MAP Kinase pathway inhibitors in pairwise combination with 58 signaling inhibitors, assaying for synergistic cytotoxicity. We found enormous diversity in the drug combinations that showed synergy, with no two cell lines having an identical profile. Although the 6 lines most resistant to BRAF inhibition showed synergistic benefit from combination with lapatinib, the signaling mechanisms by which this combination generated synergistic cytotoxicity differed between the cell lines. We conclude that adaptive responses to inhibition of the primary oncogenic driver (BRAFV600E) are determined not only by the primary oncogenic driver but also by diverse secondary genetic and epigenetic changes (“back-seat drivers”) and hence optimal drug combinations will be variable. Because upregulation of receptor tyrosine kinases is a major source of drug resistance arising from diverse adaptive responses, we propose that inhibitors of these receptors may have substantial clinical utility in combination with inhibitors of the MAP Kinase pathway. |
| Databáze: | OpenAIRE |
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