Receptor-Driven ERK Pulses Reconfigure MAPK Signaling and Enable Persistence of Drug-Adapted BRAF-Mutant Melanoma Cells
Luca Gerosa(Harvard University), Christopher Chidley(Harvard University), Fabian Fröhlich(Harvard University), Gabriela Sánchez(Harvard University), Sang Kyun Lim(Harvard University), Jeremy L. Muhlich(Harvard University), Jia-Yun Chen(Harvard University), Sreeram Vallabhaneni(Harvard University), Gregory J. Baker(Harvard University), Denis Schapiro(Broad Institute), Mariya Atanasova(Harvard University), Lily A. Chylek(Harvard University), Tujin Shi(Pacific Northwest National Laboratory), Lian Yi(Pacific Northwest National Laboratory), Carrie Nicora(Pacific Northwest National Laboratory), Allison Claas(Massachusetts Institute of Technology), Thomas S.C. Ng(Massachusetts General Hospital), Rainer H. Köhler(Massachusetts General Hospital), Douglas A. Lauffenburger(Massachusetts Institute of Technology), Ralph Weissleder(Massachusetts General Hospital), Miles A. Miller(Massachusetts General Hospital), Weijun Qian(Pacific Northwest National Laboratory), H Wiley(Pacific Northwest National Laboratory), Peter K. Sorger(Harvard University)
Cited by 115Open Access
Abstract
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.
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