Objective Colorectal cancer (CRC) kills up to 170,000 Europeans annually. Although survival rates have improved gradually, new treatment strategies are certainly needed. Hyper-activation of WNT/Beta-catenin signalling occurs in up 93% of CRC cases and MYC appears to be an obligate effector of Beta-Catenin in the gut, making MYC an attractive target for therapeutic intervention. MYC, however, is difficult to target directly, owing to its lack of enzymatic activity or obviously druggable structural features. An alternative strategy is to target the biological consequences of MYC deregulation. The Murphy lab recently showed that MYC overexpressing tumour cells in culture exhibit an ectopic dependency on a little-known kinase called ARK5/NUAK1: whereas cells lacking MYC overexpression are able to withstand NUAK1 depletion or inhibition, cells with overexpressed MYC are unable to maintain energetic homeostasis in the absence of NUAK1, deplete their ATP levels, and consequently lose viability. We have therefor 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 show 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.Based on these exciting preliminary data, I now propose to thoroughly evaluate NUAK1 as a target for therapy in CRC and to use a combination of proteomic, phosphor-proteomic and metabolomics analysis to determine the mechanism by which NUAK1 suppression erodes tumour cell viability. Fields of science medical and health sciencesbasic medicinepharmacology and pharmacydrug discoverymedical and health sciencesclinical medicineoncologycolorectal cancernatural sciencesbiological sciencesgeneticsmutationsocial scienceseconomics and businessbusiness and managementemploymentmedical and health sciencesbasic medicinephysiologyhomeostasis Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Topic(s) MSCA-IF-2015-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF) Call for proposal H2020-MSCA-IF-2015 See other projects for this call Funding Scheme MSCA-IF-EF-ST - Standard EF Coordinator UNIVERSITY OF GLASGOW Net EU contribution € 183 454,80 Address UNIVERSITY AVENUE G12 8QQ Glasgow United Kingdom See on map Region Scotland West Central Scotland Glasgow City Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 183 454,80
