title: Systematic analysis of BRAF(V600E) melanomas reveals a role for JNK/c-Jun pathway in adaptive resistance to drug-induced apoptosis.
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.
authors: HMS LINCS Center, Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
authors: Mohammad
authors: M
authors: Fallahi-Sichani
authors: HMS LINCS Center, Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
authors: Nathan J
authors: NJ
authors: Moerke
authors: HMS LINCS Center, Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
authors: Mario
authors: M
authors: Niepel
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
authors: Tinghu
authors: T
authors: Zhang
authors: Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
authors: Nathanael S
authors: NS
authors: Gray
authors: HMS LINCS Center, Department of Systems Biology, Harvard Medical School, Boston, MA, USA peter_sorger@hms.harvard.edu.
authors: Peter K
authors: PK
authors: Sorger
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D013449:Sulfonamides / Q000494:pharmacology*; D000077484:Vemurafenib
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAFV600E melanomas; RAF and MEK inhibitors; adaptive responses; cell‐to‐cell variability; submaximal drug effect