Article

TAK1 inhibition promotes apoptosis in KRAS-dependent colon cancers.

Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, MA 02129, USA.
Cell (impact factor: 32.4). 02/2012; 148(4):639-50. DOI:10.1016/j.cell.2011.12.033 pp.639-50
Source: PubMed

ABSTRACT Colon cancers frequently harbor KRAS mutations, yet only a subset of KRAS mutant colon cancer cell lines are dependent upon KRAS signaling for survival. In a screen for kinases that promote survival of KRAS-dependent colon cancer cells, we found that the TAK1 kinase (MAP3K7) is required for tumor cell viability. The induction of apoptosis by RNAi-mediated depletion or pharmacologic inhibition of TAK1 is linked to its suppression of hyperactivated Wnt signaling, evident in both endogenous and genetically reconstituted cells. In APC mutant/KRAS-dependent cells, KRAS stimulates BMP-7 secretion and BMP signaling, leading to TAK1 activation and enhancement of Wnt-dependent transcription. An in vitro-derived "TAK1 dependency signature" is enriched in primary human colon cancers with mutations in both APC and KRAS, suggesting potential clinical utility in stratifying patient populations. Together, these findings identify TAK1 inhibition as a potential therapeutic strategy for a treatment-refractory subset of colon cancers exhibiting aberrant KRAS and Wnt pathway activation.

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Keywords

aberrant KRAS
 
APC mutant/KRAS-dependent cells
 
BMP signaling
 
hyperactivated Wnt signaling
 
kinases
 
KRAS mutant colon cancer cell lines
 
KRAS signaling
 
KRAS stimulates BMP-7 secretion
 
KRAS-dependent colon cancer cells
 
mutations
 
potential clinical utility
 
potential therapeutic strategy
 
primary human colon cancers
 
RNAi-mediated depletion
 
stratifying patient populations
 
TAK1 activation
 
TAK1 kinase
 
treatment-refractory subset
 
tumor cell viability
 
Wnt pathway activation