A Ras and NF-κB pas de deux

Non-small-cell lung cancer (NSCLC) is a leading cause of cancer death worldwide. Small-molecule inhibitors that target epidermal growth factor receptor (EGFR) have shown some clinical success; however, mutations in KRAS , which are detected in 20–30% of NSCLC adenocarcinomas, render these therapeutics mostly ineffective. Two reports in Nature now demonstrate that nuclear factor-κB (NF-κB) signalling is essential for the survival of cancer cells with mutations in KRAS, revealing a potential new pathway for therapeutic intervention.

In addition to mutations in KRAS, loss of p53 activity is a frequent event in NSCLCs. Constitutively active KRAS^G12D was previously shown to stimulate the NF-κB pathway, whereas wild-type p53 antagonizes NF-κB activity. Jacks and colleagues found that localization of the NF-κB subunit p65 (also known as RELA) in mouse embryonic fibroblasts was not affected by either expression of KRAS^G12D or loss of p53. However, expression of KRAS^G12D and concomitant loss of p53 caused p65 to accumulate in the nucleus.

Tumour cells from mice that expressed KRAS^G12D and lacked p53 (KP mice) exhibited high levels of NF-κB DNA-binding activity; similar observations were made with human NSCLC cell lines. Blocking NF-κB pathway activation through the expression of a dominant-negative mutant of NF-κB inhibitor-α (IκBα; also known as NFKBIA), or knockdown of either p65 or the NF-κB pathway protein NEMO (also known as IKBKG), induced apoptosis in KP cells, but not wild-type cells. These data reveal that the canonical NF-κB pathway is important for the survival of lung cancers with mutations in KRAS and TP53 (which encodes p53). Indeed, the dominant-negative IκBα mutant blocked tumour formation and attenuated the growth of established tumours in KP mice.

A crucial role for NF-κB in cancers that express mutant KRAS was also observed by Hahn and colleagues. The authors found that TANK-binding kinase 1 (TBK1; a non-canonical IκB kinase) was required for the survival of human cancer cells that express mutant KRAS, as suppression of TBK1 induced apoptosis in these cells. Consistent with previous observations, the selective inhibition of the Ras effector RALB also induced death in KRAS-mutant cells.

Gene expression analyses revealed that the KRAS-mutant lung cancers show evidence of Ras and NF-κB pathway activation. Indeed, the levels of NFKBIA and the NF-κB precursor NFKB1 were reduced in KRAS-mutant cells, which were restored by the suppression of TBK1. Additional experiments found that mutant KRAS and TBK1 were required for the nuclear accumulation of the NF-κB subunit REL, as well as the expression of the anti-apoptotic protein BCL-X_L. Therefore, oncogenic KRAS activates RALB–TBK1 signalling to induce activation of NF-κB and promote cancer cell survival.

Together, the studies from Jacks and colleagues and Hahn and colleagues suggest that the inhibition of the NF-κB pathway might be an effective strategy for treating lung adenocarcinomas that have mutations in KRAS and p53, as well as other cancers that express constitutively active KRAS.