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

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 BRAF ^V600E 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 BRAF ^V600E 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.
Competing Interests: Declaration of Interests P.K.S. is a member of the SAB or BOD of Glencoe Software, Applied Biomath, and RareCyte and has equity in these companies and is on the SAB of and NanoString. In the last five years the Sorger lab has received research funding from Novartis and Merck. P.K.S. declares that none of these relationships are directly or indirectly related to the content of this manuscript. R.W. is a co-founder of T2Biosystems and Lumicell, serves as a scientific advisor for ModeRNA Therapeutics, Tarveda Therapeutics, and Alivio Therapeutics. None of these activities are related to the manuscript. The other authors declare that they have no competing interests.
(Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)