Journal
CELL SYSTEMS
Volume 11, Issue 5, Pages 478-+Publisher
CELL PRESS
DOI: 10.1016/j.cels.2020.10.002
Keywords
-
Categories
Funding
- NCI [U54-CA225088, U54-CA210180, U01-CA227544, P41-GM103493, R00-CA207744, U01-CA206997]
- Novartis Foundation
- HFSP grant [LT000259/2019-L1]
- SNSF Early Postdoc Mobility fellowship [P2ZHP3_181475]
- DOE [DE-AC05-76RL0 1830]
- Swiss National Science Foundation (SNF) [P2ZHP3_181475] Funding Source: Swiss National Science Foundation (SNF)
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available