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

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

  • Cell Syst. 2020 Nov 18;11(5):478-494.e9. doi: 10.1016/j.cels.2020.10.002.
Luca Gerosa 1 Christopher Chidley 1 Fabian Fröhlich 1 Gabriela Sanchez 1 Sang Kyun Lim 1 Jeremy Muhlich 1 Jia-Yun Chen 1 Sreeram Vallabhaneni 1 Gregory J Baker 1 Denis Schapiro 2 Mariya I Atanasova 1 Lily A Chylek 1 Tujin Shi 3 Lian Yi 3 Carrie D Nicora 3 Allison Claas 4 Thomas S C Ng 5 Rainer H Kohler 5 Douglas A Lauffenburger 4 Ralph Weissleder 5 Miles A Miller 5 Wei-Jun Qian 3 H Steven Wiley 6 Peter K Sorger 7
Affiliations

Affiliations

  • 1 Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 2 Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 3 Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA.
  • 4 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • 5 Center for Systems Biology, Massachusetts General Hospital Research Institute, Boston, MA 02114, USA.
  • 6 Environmental Molecular Sciences Laboratory, Pacific Northwest National Laboratory, Richland, WA 99354, USA.
  • 7 Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: peter_sorger@hms.harvard.edu.
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.

Keywords

BRAF(V600E) melanoma; MAPK pathway; cancer persistence; kinase inhibitors; kinetic modeling; non-genetic drug resistance; signaling plasticity; systems pharmacology; targeted therapy.

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