LINCSapplication/xmlhttp://lincsportal.ccs.miami.edu/dcic/api/download?path=LINCS_Data/HMS_LINCS&file=LDS-1221.tar.gzprimaryOK200UnknownMultiomicsMohammad Fallahi-SichaniNIH 1U54HG006097-01; NIH 1U54HL127365-01Fluorescence imagingFluorescence intensityRPPAhttp://lincsportal.ccs.miami.edu/datasets/#/view/LDS-1221HMS LINCS (Harvard Medical School)This dataset presents an analysis of the variable importance in the projection (VIP) scores for each variable in the partial-least-squares regression (PLSR) models arising from analysis of HMS LINCS datasets #20217 and 20218, which assess covariation of molecular signals (measured by RPPA; dataset #20218) with cellular responses (relative viability and apoptotic fractions; dataset #20217). pMEK and pERK signals were excluded from the analysis.LINCSDrugs 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.Systematic analysis of BRAF(V600E) melanomas reveals a role for JNK/c-Jun pathway in adaptive resistance to drug-induced apoptosis.Fallahi-Sichani Mohammad M, Moerke Nathan J NJ, Niepel Mario M, Zhang Tinghu T, Gray Nathanael S NS, Sorger Peter K PKfalseAverage variable importance in the projection (VIP) scores from the PLSR models analyzing the covariation of molecular signals with cell viability and apoptosis fraction in BRAF(V600E/D) melanoma cell lines-2015-09-232015-09-23LDS-122125814555