Title | Receptor-Driven ERK Pulses Reconfigure MAPK Signaling and Enable Persistence of Drug-Adapted BRAF-Mutant Melanoma Cells. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | 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 |
Journal | Cell Syst |
Volume | 11 |
Issue | 5 |
Pagination | 478-494.e9 |
Date Published | 2020 11 18 |
ISSN | 2405-4720 |
Keywords | 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 |
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 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. |
DOI | 10.1016/j.cels.2020.10.002 |
Alternate Journal | Cell Syst |
PubMed ID | 33113355 |
PubMed Central ID | PMC8009031 |
Grant List | 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 |