Combinatorial drug screening and molecular profiling reveal diverse mechanisms of intrinsic and adaptive resistance to BRAF inhibition in V600E BRAF mutant melanomas
Metrics: PDF 973 views | HTML 1397 views | ?
Devin G. Roller1, Brian Capaldo2, Stefan Bekiranov2, Aaron J. Mackey3, Mark R. Conaway3, Emanuel F. Petricoin4, Daniel Gioeli1, Michael J. Weber1
1Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, 22908 USA
2Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, 22908 USA
3Department of Public Health Sciences, University of Virginia, Charlottesville, VA, 22908 USA
4Center for Applied Proteomics and Molecular Medicine, School of Systems Biology, College of Science, George Mason University, Manassas, VA 20110, USA
Michael J. Weber, e-mail: email@example.com
Keywords: melanoma, therapeutic resistance, cell signaling, BRAF, MAP Kinase
Received: August 20, 2015 Accepted: November 21, 2015 Published: December 10, 2015
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-naïve 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.
All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.