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
  • 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: [email protected].
PMID: 33113355 DOI: 10.1016/j.cels.2020.10.002
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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