RAS is one of the most commonly mutated gene families in human cancers – one of its three members (KRAS, HRAS and NRAS) is mutated in about 20% of human tumours. Attempts to target mutant RAS proteins directly with small-molecule inhibitors have so far proved unsuccessful, so there has been considerable interest in finding signalling pathways that function downstream of RAS and whose blockade might be selectively toxic to tumour cells. Two papers in Nature 5th November 2009 provide evidence that targeting one such pathway, the NF- KB signalling pathway, may be an effective approach to treat RAS-mutant tumours such as lung cancers. Barbie et al.’ (page 108) identify a component of the NF-KB pathway as a potential target in RAS-mutant cancer cells, and Meylan et al’ (page 104) show that inhibition of NF-KB signalling impairs tumour formation in a mouse model ofRAS-induced lung cancer. The NF-KB transcriptional program control is a multitude of cell functions, most notably the regulation of cell death and inflammation
The use of the RNA-interference technique to selectively inhibit gene expression, together with knowledge of the full sequence of the human genome, has made possible large-scale functional genomic screens. In these, each gene in the genome (or at least a significant proportion of genes) is silenced one by one, and the effect on cell function is assayed. This approach has recently been used to investigate which genes, when silenced, kill cells bearing mutant RAS but not cells that lack this mutation so-called synthetic lethal interactions. Barbie et al’ looked for synthetic lethal interactions in a panel of cell lines, some of which had activating mutations in KRAS. The authors inhibited genes thought to be important for the development of cancer and identified several genes whose reduced activity seemed to selectively kill the RAS-mutant cells. After KRAS itself, silencing the gene TBK1, an upstream regulator of the NF-KB pathway, was most effective for selectively killing RAS-mutant cells. TBK1 is thought to activate NF-KB by phosphorylating IKB, an F-KB inhibitor. It also activates other transcription factors involved in inflammatory responses, such as IRF3 and IRF7 .
Downward 2009 A tumour gene’s fatal flaws Nature vol 462 pp 44-45

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