Mutations in RAS genes are common in human tumours, but RAS has proved impossible to target with drugs. Its associated NF-κB signalling pathway, however, may turn out to be this tumour gene's Achilles heel.
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 this issue provide evidence that targeting one such pathway, the NF-κB signalling pathway, may be an effective approach to treat RAS-mutant tumours such as lung cancers. Barbie et al.1 (page 108) identify a component of the NF-κB pathway as a potential target in RAS-mutant cancer cells, and Meylan et al.2 (page 104) show that inhibition of NF-κB signalling impairs tumour formation in a mouse model of RAS-induced lung cancer.
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 used3,4 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.1 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-κB pathway, was most effective for selectively killing RAS-mutant cells. TBK1 is thought to activate NF-κB by phosphorylating IκB, an NF-κB inhibitor. It also activates other transcription factors involved in inflammatory responses, such as IRF3 and IRF7 (ref. 5).
The NF-κB transcriptional program controls a multitude of cell functions, most notably the regulation of cell death and inflammation6. This is by no means the first time that this pathway has been linked to RAS-mediated tumour formation. NF-κB signalling has been shown7 to suppress the tendency of mutant RAS to cause stress-induced cell death, in part by undermining cell-cycle checkpoints. Indeed, TBK1 has been shown8 to have a crucial role downstream of RAS, being activated by RalB, a small GTP-binding protein that is controlled by RalGDS, one of the downstream effectors of RAS (Fig. 1).
The finding that RAS-mutant cells are dependent on TBK1 in vitro indicates that it would make sense to attempt to inhibit the NF-κB pathway in these tumour types. However, the links between NF-κB and the inflammatory response, together with our growing awareness of the importance of inflammation in the pathogenesis of cancer6, suggest that the role of NF-κB in cancer is probably poorly modelled by tissue-culture experiments using homogeneous cell populations. What has been lacking so far are data from an animal model of cancer that is characterized by RAS mutation. These data have now been provided by Meylan and colleagues2. The authors engineered mice in which the mutated cancer-promoting gene (oncogene) KRAS is expressed at the same time as the p53 tumour-suppressor gene is deleted in the lung; the result is the development of an aggressive lung cancer. Simultaneous expression of an inhibitor of the NF-κB pathway, the IκB 'super repressor', causes a massive reduction in the number and size of lung tumours formed. Also, inhibition of NF-κB in established lung tumours using an inducible form of the IκB super repressor slowed their growth, although tumours did not regress.
The results of this first foray into the targeting of NF-κB in KRAS-mutant lung tumours are encouraging, but much remains to be done before we can assess the likelihood of the success of this approach in the clinic. The failure to cause regression of existing tumours compares unfavourably with studies using other inhibitors; for instance, a combination of small-molecule inhibitors targeting two major RAS-effector pathways, MEK and PI3-kinase (Fig. 1), caused regression of similar KRAS-induced lung tumours9. Small-molecule inhibitors have been developed against the NF-κB pathway — it will be interesting to see how these perform in Meylan and colleagues' mouse model2.
A consistent worry with targeting NF-κB in cancer has been that prolonged inhibition of the pathway will cause immunosuppression, so it may be necessary to limit the length and frequency of systemic treatments with such inhibitors. This was not an issue for Meylan and colleagues2, as the IκB super repressor is expressed only in tumour cells. Another concern is the harmful effects reported when NF-κB is suppressed in some tumour types, including one mouse model of human skin cancer driven by an activated RAS oncogene, in which inhibition of NF-κB led to tumour progression, rather than its regression10.
An issue worth considering is whether targeting TBK1 might have unique advantages over other ways of inhibiting NF-κB signalling in RAS-mutant tumours. This question is difficult to answer right now, as the pathway displays considerable complexity and the function of some of the lesser-known components, such as TBK1, is still relatively poorly understood. However, the work of Barbie et al.1 and Meylan et al.2 clearly establish the importance of NF-κB signalling in RAS-induced tumour formation, and highlight the potential value of pharmacological targeting of this pathway in lung and possibly other common cancers.
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