The targeting of oncogenes has led to the development of several molecularly targeted therapies. However, most known oncogenes such as KRAS and tumor suppressors have proven to be challenging therapeutic targets. An alternative approach to direct targeting of known cancer alleles is to exploit the genetic concept of synthetic lethality, in which gene products are identified that, when suppressed or inhibited, result in cell death only in the presence of another nonlethal mutation. Over the past several years, we have developed genome scale RNAi libraries that permit a systematic evaluation of genes involved in cancer initiation and maintenance. Using these libraries, we have now performed screens in a panel of human cancer cell lines to systematically identify cancer vulnerabilities. By combining these functional approaches with information derived from mapping the structural abnormalities present in cancer genomes, we have identified several genes that act as synthetic lethal partners to KRAS including the serine-threonine kinase TBK1. In recent work, we have solved the structure of TBK1 in complex with a nanomolar TBK1 inhibitor and explored the activity of TBK1 inhibitors on KRAS dependent cancers. TBK1 is regulated by K63 ubiquitination and has multiple substrates that contribute to KRAS synthetic lethality. These observations confirm the role of TBK1 and NF-kB signaling in KRAS-dependent cancers and provide a foundation for translational studies.
Citation Format: William C. Hahn. Functional genomics and KRAS-driven cancers. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr IA11.