Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1

By D. Barbie, Pablo Tamayo, J. Boehm, S. Kim, S. Moody, I. Dunn, Anna C. Schinzel, P. Sandy, E. Meylan, C. Scholl and 25 more. Nature, 2009

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The proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. Although the identification of specific oncogenes has led to the development of clinically effective, molecularly targeted therapies in some cases, KRAS has remained refractory to this approach. A complementary strategy for targeting KRAS is to identify gene products that, when inhibited, result in cell death only in the presence of an oncogenic allele. Here we have used systematic RNA interference to detect synthetic lethal partners of oncogenic KRAS and found that the non-canonical IκB kinase TBK1 was selectively essential in cells that contain mutant KRAS. Suppression of TBK1 induced apoptosis specifically in human cancer cell lines that depend on oncogenic KRAS expression. In these cells, TBK1 activated NF-κB anti-apoptotic signals involving c-Rel and BCL-XL (also known as BCL2L1) that were essential for survival, providing mechanistic insights into this synthetic lethal interaction. These observations indicate that TBK1 and NF-κB signalling are essential in KRAS mutant tumours, and establish a general approach for the rational identification of co-dependent pathways in cancer.

Subfields: Cancer Research, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/161d9631eed25724e7d8c609081da93718198cc2

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Citations in the corpus

Molecular and genetic properties of tumors associated with local immune cytolytic activity (2015, positive): “Marker genes for specific cell types were identified as those with expression at least 2-fold greater than observed in any other cell type (using Fantom5 and DMAP), and enrichment was calculated using ssGSEA (Barbie et al., 2009).”
An integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR and NF1 (2010, methodology): “A statistic was calculated by an integration of the difference between the ECDFs, which is similar to the one used in Gene Set Enrichment Analysis but based on absolute expression rather than differential expression (Barbie et al., 2009).”
Pattern recognition receptors and inflammation. (2010, background): “Furthermore, a recent study revealed that TBK1 is required for KRAS-driven cancer formation, probably by activating the NF-kB-induced antiapoptotic gene BCL-xL (Barbie et al., 2009).”
Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor. (2018, background): “The largest cluster with significant downregulation composed a KRAS-regulated network enriched of genes linked to transformation by oncogenic KRAS (Barbie et al., 2009; Chiaradonna et al., 2006; Liberzon et al., 2015), such as E2F transcription factors (Liberzon et al.”
GSVA: gene set variation analysis for microarray and RNA-Seq data (2013, methodology): “Three unsupervised, single sample enrichment methods have been developed, Pathway Level analysis of Gene Expression (PLAGE), single sample GSEA (ssGSEA) and the combined z-score [5,22,35].”
Targeting the cancer kinome through polypharmacology (2010, positive): “Barbie et al. 74 screened a panel of shRNAs targeting kinases, phosphatases and onco-genes against a panel of 19 tumour cell lines and then extracted from these data the genes selectively required for the survival of KRAS -mutant cells 74 .”