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Cell Syst ; 11(5): 478-494.e9, 2020 11 18.
Article in English | MEDLINE | ID: mdl-33113355

ABSTRACT

Targeted inhibition of oncogenic pathways can be highly effective in halting the rapid growth of tumors but often leads to the emergence of slowly dividing persister cells, which constitute a reservoir for the selection of drug-resistant clones. In BRAFV600E melanomas, RAF and MEK inhibitors efficiently block oncogenic signaling, but persister cells emerge. Here, we show that persister cells escape drug-induced cell-cycle arrest via brief, sporadic ERK pulses generated by transmembrane receptors and growth factors operating in an autocrine/paracrine manner. Quantitative proteomics and computational modeling show that ERK pulsing is enabled by rewiring of mitogen-activated protein kinase (MAPK) signaling: from an oncogenic BRAFV600E monomer-driven configuration that is drug sensitive to a receptor-driven configuration that involves Ras-GTP and RAF dimers and is highly resistant to RAF and MEK inhibitors. Altogether, this work shows that pulsatile MAPK activation by factors in the microenvironment generates a persistent population of melanoma cells that rewires MAPK signaling to sustain non-genetic drug resistance.


Subject(s)
MAP Kinase Signaling System/physiology , Melanoma/metabolism , Proto-Oncogene Proteins B-raf/metabolism , Cell Line, Tumor , Drug Resistance, Neoplasm/drug effects , Extracellular Signal-Regulated MAP Kinases/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Humans , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/genetics , Melanoma/genetics , Mitogen-Activated Protein Kinase Kinases/metabolism , Mutation/drug effects , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/physiology , Signal Transduction/drug effects , Tumor Microenvironment/drug effects , ras Proteins/genetics
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