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TAK1 is required for survival in KRAS-dependent colorectal cancer
▶ Singh A, Sweeney MF, Yu M, et al. TAK1 inhibition promotes apoptosis in KRAS-dependent colon cancers. Cell 2012;148:639–50.
Mutation of KRAS is common in the pathogenesis of colorectal cancer and predicts resistance to epidermal growth factor receptor inhibition as a treatment strategy. The cellular effect of mutated KRAS is complex and is known to be linked to both the Wnt and TGFβ signalling pathways. Studies in colorectal cancer cell lines suggest that only around half of KRAS-mutated cell lines are dependent on KRAS expression for survival. Cellular effectors of KRAS dependency remain largely undetermined. Using KRAS-dependent and -independent colorectal cancer cell lines, Singh and colleagues identified a KRAS dependency gene expression set by microarray. Hierarchical clustering and ontology analyses demonstrated enrichment for kinases and Wnt signalling components in KRAS-dependent cells. Selected kinases were targeted for disrupted expression in two cell lines by shRNA. Depletion of the kinase, TAK1, had the most potent effect on the viability of the KRAS-dependent versus the -independent cell line. KRAS-dependent cell lines displayed sensitivity to the selective TAK1 inhibitor, 5Z-7-oxozeaenol. Furthermore, in a xenograft model, 5Z-7-oxozeaenol resulted in regression of KRAS-dependent tumours without obvious toxicity. Further experimental data presented by Singh and colleagues demonstrate that antiapoptotic signalling in KRAS-dependent cells involves autocrine BMP signalling, which activates TAK1, in turn driving Wnt signalling in the absence of functional APC. These findings suggest that non-oncogene effectors of KRAS-dependency, such as TAK1, represent therapeutic targets in a subset of colorectal cancers.
Understanding the signals controlling hepatic progenitor cell fate in chronic liver disease
▶ Boulter L, Govaere O, Bird TG, et al. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nat Med. Published Online First: 4 March 2012. doi:10.1038/nm.2667
Hepatic Progenitor Cells (HPCs) are bipotential cells which, depending on the nature of injury, are capable of differentiating into either …
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