Receptor-Driven ERK Pulses Reconfigure MAPK Signaling and Enable Persistence of Drug-Adapted BRAF-Mutant Melanoma Cells

• DOI: 10.1016/j.cels.2020.10.002
• Publication Date: 2020-10-27T14:32:59Z
• Authors: Luca Gerosa; Christopher Chidley; Fabian Fröhlich; Gabriela Sanchez; Sang Kyun Lim; Jeremy Muhlich; Jia-Yun Chen; Sreeram Vallabhaneni; Gregory J. Baker; Denis Schapiro; Mariya I. Atanasova; Lily A. Chylek; Tujin Shi; Lian Yi; Carrie D. Nicora; Allison Claas; Thomas S.C. Ng; Rainer H. Kohler; Douglas A. Lauffe...; Ralph Weissleder; Miles A. Miller; Wei-Jun Qian; H. Steven Wiley; Peter K. Sorger
• Keywords: Mitogen-Activated Protein Kinase Kinases; Proto-Oncogene Proteins B-raf; 0303 health sciences; MAP Kinase Signaling System; Gene Expression Regulation, Neoplastic; 03 medical and health sciences; Drug Resistance, Neoplasm; Cell Line, Tumor; Mutation; Tumor Microenvironment; ras Proteins; Humans; Extracellular Signal-Regulated MAP Kinases; Melanoma; Protein Kinase Inhibitors; Signal Transduction

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