Cancer: a Ras and NF-Κb Pas De Deux

ReseaRch highlights

cancer A Ras and NF-κB pas de deux Non-small-cell lung cancer (NSCLC) pathway protein NEMO (also known Together, the studies from Jacks is a leading cause of cancer death as IKBKG), induced apoptosis in KP and colleagues and Hahn and worldwide. Small-molecule inhibi- cells, but not wild-type cells. These colleagues suggest that the inhibition tors that target epidermal growth data reveal that the canonical NF-κB of the NF-κB pathway might be an factor receptor (EGFR) have shown pathway is important for the survival effective strategy for treating lung some clinical success; however, of lung cancers with mutations in adenocarcinomas that have mutations mutations in KRAS, which are KRAS and TP53 (which encodes p53). in KRAS and p53, as well as other detected in 20–30% of NSCLC Indeed, the dominant-negative IκBα cancers that express constitutively adenocarcinomas, render these mutant blocked tumour formation active KRAS. therapeutics mostly ineffective. and attenuated the growth of Emily J. Chenette Two reports in Nature now demon- established tumours in KP mice. UCSD–Nature Signaling Gateway strate that nuclear factor-κB (NF-κB) A crucial role for NF-κB in signalling is essential for the survival cancers that express mutant KRAS Original research PaPers Meylan, E. et al. Requirement for NF-κB signalling in a mouse of cancer cells with mutations in was also observed by Hahn and model of lung adenocarcinoma. Nature 462, KRAS, revealing a potential new colleagues. The authors found that 104–107 (2009) | Barbie, D. A. et al. Systematic pathway for therapeutic intervention. TANK-binding kinase 1 (TBK1; RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462, In addition to mutations in KRAS, a non-canonical IκB kinase) was 108–112 (2009) loss of p53 activity is a frequent event required for the survival of human in NSCLCs. Constitutively active cancer cells that express mutant KRASG12D was previously shown KRAS, as suppression of TBK1 to stimulate the NF-κB pathway, induced apoptosis in these cells. whereas wild-type p53 antagonizes Consistent with previous observa- NF-κB activity. Jacks and colleagues tions, the selective inhibition of the found that localization of the NF-κB Ras effector RALB also induced subunit p65 (also known as RELA) death in KRAS-mutant cells. in mouse embryonic fibroblasts was Gene expression analyses revealed not affected by either expression of that the KRAS-mutant lung cancers KRASG12D or loss of p53. However, show evidence of Ras and NF-κB expression of KRASG12D and con- pathway activation. Indeed, the comitant loss of p53 caused p65 to levels of NFKBIA and the NF-κB accumulate in the nucleus. precursor NFKB1 were reduced in Tumour cells from mice that KRAS-mutant cells, which were expressed KRASG12D and lacked restored by the suppression of TBK1. p53 (KP mice) exhibited high levels Additional experiments found of NF-κB DNA-binding activity; that mutant KRAS and TBK1 were similar observations were made with required for the nuclear accumulation human NSCLC cell lines. Blocking of the NF-κB subunit REL, as well as NF-κB pathway activation through the expression of the anti-apoptotic

the expression of a dominant-negative protein BCL-XL. Therefore, oncogenic mutant of NF-κB inhibitor-α (IκBα; KRAS activates RALB–TBK1 signal- also known as NFKBIA), or knock- ling to induce activation of NF-κB down of either p65 or the NF-κB and promote cancer cell survival.