|Receptor-Driven ERK Pulses Reconfigure MAPK Signaling and Enable Persistence of Drug-Adapted BRAF-Mutant Melanoma Cells.
|Year of Publication
|Gerosa L, Chidley C, Fröhlich F, Sanchez G, Lim SKyun, Muhlich J, Chen J-Y, 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 W-J, H Wiley S, Sorger PK
|2020 11 18
|Cell Line, Tumor, Drug Resistance, Neoplasm, Extracellular Signal-Regulated MAP Kinases, Gene Expression Regulation, Neoplastic, Humans, MAP Kinase Signaling System, Melanoma, Mitogen-Activated Protein Kinase Kinases, Mutation, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, ras Proteins, Signal Transduction, Tumor Microenvironment
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 BRAF 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 BRAF 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.
|PubMed Central ID
|U01 CA206997 / CA / NCI NIH HHS / United States
U54 CA210180 / CA / NCI NIH HHS / United States
U54 CA225088 / CA / NCI NIH HHS / United States
P41 GM103493 / GM / NIGMS NIH HHS / United States
R00 CA207744 / CA / NCI NIH HHS / United States
U01 CA227544 / CA / NCI NIH HHS / United States