{"database":"LINCS","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["http://lincsportal.ccs.miami.edu/dcic/api/download?path=LINCS_Data/HMS_LINCS&file=LDS-1220.tar.gz"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Unknown","Multiomics"],"submitter":["Mohammad Fallahi-Sichani"],"funding":["1U54HL127365-01"],"technology_type":["Fluorescence imaging","Fluorescence intensity","RPPA"],"full_dataset_link":["http://lincsportal.ccs.miami.edu/datasets/#/view/LDS-1220"],"submitter_affiliation":["HMS LINCS (Harvard Medical School)"],"sample_protocol":["This analysis dataset presents partial-least-squares regression (PLSR) model loadings arising from analysis of HMS LINCS datasets #20217 and 20218 for covariation of molecular signals (measured by RPPA; dataset #20218) with cellular responses (relative viability and apoptotic fractions; datasets #20217) when pMEK and pERK signals are excluded."],"repository":["LINCS"],"data_protocol":[""],"pubmed_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."],"pubmed_title":["Systematic analysis of BRAF(V600E) melanomas reveals a role for JNK/c-Jun pathway in adaptive resistance to drug-induced apoptosis."],"pubmed_authors":["Fallahi-Sichani Mohammad M, Moerke Nathan J NJ, Niepel Mario M, Zhang Tinghu T, Gray Nathanael S NS, Sorger Peter K PK"],"additional_accession":[]},"is_claimable":false,"name":"PLSR model loadings (pMEK and pERK excluded) from analysis of the covariation of molecular signals with cell viability and apoptosis fraction in BRAF(V600E/D) melanoma cell lines","description":"-","dates":{"publication":"2015-09-23","updated":"2015-09-23"},"accession":"LDS-1220","cross_references":{"pubmed":["25814555"]}}