{"database":"biostudies-other","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"submitter":["Prof Peter, K Sorger"],"journal":["Molecular Systems Biology"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-SCDT-62817_2_1425480741"],"abstract":["Drugs that inhibit RAF/MEK signaling, such as vemurafenib, elicit profound but often temporary anti-tumor responses in patients with BRAFV600E melanoma. Adaptive responses to RAF/MEK inhibition occur on a time scale 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."],"repository":["biostudies-other"],"pubmed_authors":["Prof Peter, K Sorger","Dr Nathan Moerke","Dr Tinghu Zhang","Dr Mohammad Fallahi-Sichani","Dr Nathanael, Schiander Gray","Dr Mario Niepel"],"additional_accession":[]},"is_claimable":false,"name":"Systematic analysis of BRAF(V600E) melanomas reveals a role for JNK/c-Jun pathway in adaptive resistance to drug-induced apoptosis.","description":"Drugs that inhibit RAF/MEK signaling, such as vemurafenib, elicit profound but often temporary anti-tumor responses in patients with BRAFV600E melanoma. Adaptive responses to RAF/MEK inhibition occur on a time scale 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.","dates":{"modification":"2019-01-17T21:00:03Z","creation":"2019-01-17T21:00:03Z"},"accession":"S-SCDT-62817_2_1425480741","cross_references":{"doi":["10.15252/msb.20145877"]}}