Receptor-Driven ERK Pulses Reconfigure MAPK Signaling and Enable Persistence of Drug-Adapted BRAF-Mutant Melanoma Cells
Luca Gerosa, Christopher Chidley, Fabian Fröhlich, Gabriela Sánchez, Sang Kyun Lim, Jeremy L. Muhlich, Jia-Yun Chen, Sreeram Vallabhaneni, Gregory J. Baker, Denis Schapiro, Mariya Atanasova, Lily A. Chylek, Tujin Shi, Lian Yi, Carrie Nicora, Allison Claas, Thomas S.C. Ng, Rainer H. Köhler, Douglas A. Lauffenburger, Ralph Weissleder, Miles A. Miller, Weijun Qian, H Wiley, Peter K. Sorger
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.