@article {924541,
	title = {Systematic analysis of BRAF(V600E) melanomas reveals a role for JNK/c-Jun pathway in adaptive resistance to drug-induced apoptosis.},
	journal = {Mol Syst Biol},
	volume = {11},
	number = {3},
	year = {2015},
	month = {2015 Mar},
	pages = {797},
	abstract = {Drugs that inhibit RAF/MEK signaling, such as vemurafenib, elicit profound but often temporary anti-tumor responses in patients with BRAF(V) (600E) melanoma. Adaptive responses to RAF/MEK inhibition occur on a timescale of hours to days, involve homeostatic responses that reactivate MAP kinase signaling and compensatory mitogenic pathways, and attenuate the anti-tumor effects of RAF/MEK inhibitors. We profile adaptive responses across a panel of melanoma cell lines using multiplex biochemical measurement, single-cell assays, and statistical modeling and show that adaptation involves at least six signaling cascades that act to reduce drug potency (IC50) and maximal effect (i.e., Emax~<<~1). Among these cascades, we identify a role for JNK/c-Jun signaling in vemurafenib adaptation and show that RAF and JNK inhibitors synergize in cell killing. This arises because JNK inhibition prevents a subset of cells in a cycling population from becoming quiescent upon vemurafenib treatment, thereby reducing drug Emax. Our findings demonstrate the breadth and diversity of adaptive responses to RAF/MEK inhibition and a means to identify which steps in a signaling cascade are most predictive of phenotypic response.},
	keywords = {Apoptosis, Cell Line, Tumor, Cell Survival, Drug Resistance, Neoplasm, Drug Synergism, Humans, Indoles, MAP Kinase Signaling System, Melanoma, Mutation, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Sulfonamides},
	issn = {1744-4292},
	doi = {10.15252/msb.20145877},
	author = {Fallahi-Sichani, Mohammad and Moerke, Nathan J and Niepel, Mario and Zhang, Tinghu and Gray, Nathanael S and Sorger, Peter K}
}
