NuSiCC · Modelling the therapeutic potential of NUAK1 suppression in colorectal cancer

Modelling the therapeutic potential of NUAK1 suppression in colorectal cancer

"Colorectal cancer (CRC) kills up to 170,000 Europeans annually. Although 10-year survival rates have increased at a reasonably steady rate, resistance to therapy is an ongoing concern and new therapies are certainly needed. Colorectal cancer is somewhat unique in that the mutations that commonly drive the disease coalesce around a limited number of well-defined genetic pathways, and the Cancer Genome Atlas project has shown that increased activity of the MYC oncogene in particular appears to be a unifying feature of the disease. MYC however is a poor target for direct pharmacological inhibition. We have therefore sought to identify indirect means of exploiting the consequences of MYC deregulation, rather than targeting MYC itself. The concept of ""synthetic lethality"" offers one such approach: Synthetic lethality is said to exist when mutation in either one of a pair of genes is tolerable but simultaneous mutation of both kills the cell. Synthetic dosage lethality is conceptually similar, except that one of the genes may be overexpressed rather than mutated. Our previous work identified a synthetic dosage lethal interaction between MYC and a little-known kinase called NUAK1: we demonstrated that cancer cells overexpressing MYC are highly dependent upon co-expression of NUAK1 and thereby highly sensitive to suppression of NUAK1. Because NUAK1 appears to be an excellent target for small molecule inhibition, the implication is thus that it may be possible to kill tumour cells that overexpress MYC by inhibiting NUAK1. Inhibitors of NUAK1 are presently at an early stage of development that precludes directly testing this concept in vivo. We have therefore taken a genetic approach to examine the requirement for NUAK1 during tumour development in a genetically engineered mouse model of sporadic Beta-Catenin-driven CRC. Our preliminary results showed that NUAK1 is required for CR tumour initiation and, more importantly, that NUAK1 depletion shrinks pre-existing tumours, suggesting that NUAK1 is an excellent candidate target for treatment of CRC. Hence, the main objectives of the project were to thoroughly evaluate NUAK1 as a target for therapy in CRC and to use a combination of proteomic, phosphor-proteomic and metabolomic analysis to determine the mechanism by which NUAK1 suppression erodes tumour cell viability. "

Data: CORDIS, © European Union