RRC ID 63143
Author Gerosa L, Chidley C, Fröhlich F, Sanchez G, Lim SK, Muhlich J, Chen JY, Vallabhaneni S, Baker GJ, Schapiro D, Atanasova MI, Chylek LA, Shi T, Yi L, Nicora CD, Claas A, Ng TSC, Kohler RH, Lauffenburger DA, Weissleder R, Miller MA, Qian WJ, Wiley HS, Sorger PK.
Title Receptor-Driven ERK Pulses Reconfigure MAPK Signaling and Enable Persistence of Drug-Adapted BRAF-Mutant Melanoma Cells.
Journal Cell Syst
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.
Volume 11(5)
Pages 478-494.e9
Published 2020-11-18
DOI 10.1016/j.cels.2020.10.002
PII S2405-4712(20)30370-7
PMID 33113355
PMC PMC8009031
MeSH 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 MAP Kinase Signaling System / physiology* Melanoma / genetics Melanoma / metabolism* Mitogen-Activated Protein Kinase Kinases / metabolism Mutation / drug effects Protein Kinase Inhibitors / pharmacology Proto-Oncogene Proteins B-raf / genetics Proto-Oncogene Proteins B-raf / metabolism* Proto-Oncogene Proteins B-raf / physiology Signal Transduction / drug effects Tumor Microenvironment / drug effects ras Proteins / genetics
IF 8.673
Human and Animal Cells MMAc·SF(RCB1200)