Synapse - MAPK pathway activation selectively inhibits ASCL1-driven small cell lung cancer

MAPK pathway activation selectively inhibits ASCL1-driven small cell lung cancer Journal Article

Authors:	Caeser, R.; Hulton, C.; Costa, E.; Durani, V.; Little, M.; Chen, X.; Tischfield, S. E.; Asher, M.; Kombak, F. E.; Chavan, S. S.; Shah, N. S.; Ciampricotti, M.; de Stanchina, E.; Poirier, J. T.; Rudin, C. M.; Sen, T.
Article Title:	MAPK pathway activation selectively inhibits ASCL1-driven small cell lung cancer
Abstract:	Activation of mitogenic signaling pathways is a common oncogenic driver of many solid tumors including lung cancer. Although activating mutations in the mitogen-activated protein kinase (MAPK) pathway are prevalent in non-small cell lung cancers, MAPK pathway activity, counterintuitively, is relatively suppressed in the more aggressively proliferative small cell lung cancer (SCLC). Here, we elucidate the role of the MAPK pathway and how it interacts with other signaling pathways in SCLC. We find that the most common SCLC subtype, SCLC-A associated with high expression of ASCL1, is selectively sensitive to MAPK activation in vitro and in vivo through induction of cell-cycle arrest and senescence. We show strong upregulation of ERK negative feedback regulators and STAT signaling upon MAPK activation in SCLC-A lines. These findings provide insight into the complexity of signaling networks in SCLC and suggest subtype specific mitogenic vulnerabilities.
Keywords:	phenotype; yap1; ras; therapeutic target; transformation; heterogeneity; subtype; cycle arrest; ascl1; neurod1
Journal Title:	iScience
Volume:	24
Issue:	11
ISSN:	2589-0042
Publisher:	Cell Press
Date Published:	2021-11-19
Start Page:	103224
Language:	English
ACCESSION:	WOS:000723606400004
DOI:	10.1016/j.isci.2021.103224
PROVIDER:	wos
PMCID:	PMC8528729
PUBMED:	34712921
Notes:	Article -- Source: Wos