Systematic high-throughput analysis of oncogenicity of human oncogene mutations

Coordinator:		PD Dr. Roman Thomas
Institution:		Max-Planck-Institut für Neurologische Forschung und Centrum für Integrierte Onkologie Köln – Bonn & Klinik I für Innere Medizin, Universität zu Köln
Homepage:		www.mpin-koeln.mpg.de

The aim of this subproject is the exploration of oncogenic transformation in mutants from multiple protein classes in cellular model systems. For this purpose we will use an initial compendium of at least 100 different human oncogene mutations covering the classes of receptor tyrosine kinases (RTKs), Ras family of small GTPases, serine-threonine kinases (STKs) and lipid kinases. The mutations were chosen in order to represent the most prevalent (e.g., mutations in KRAS, PIK3CA) or clinically relevant mutations (e.g., KRAS, EGFR) and represent different protein classes of oncogenes. The results of this approach are crucial for unrevealing oncogenic pathway dependencies and furthermore to guide the development of novel therapeutics. Recently the co-occurrence of dominant oncogene mutations where shown and we will explore the extent to which these mutations drive tumorigenesis independently and jointly. Finally, we will explore to which degree different classes of oncogene mutations are dependent on signalling through some of the major oncogenic signalling pathways, namely the Ras/ Raf/ Mek/ Erk-, the Pi3-kinase/ Akt-, and the mTOR-pathways.
Looking at the increasing number of cancer genome re-sequencing projects, such systematic efforts will be essential for translating tumor genetic information into functional understanding. In this context, a central aspect of our subproject is the establishment of a technological framework to enable a functional characterisation of somatic mutations in high throughput. Furthermore, we will create a collection of mutant cells which will subsequently used for further analyses of oncogenic signalling and small organic molecule perturbations.
The results of these studies will therefore form the basis for targeted drug development and for triggering appropriate early clinical investigation. The discovery of shared and distinct oncogenic signalling pathway dependencies may enable the identification of targets for which targeted therapeutics are already available. For example, the identification of the dependency of KRAS mutation on activation on the Pi-3-kinase or Mek-Erk signalling pathways could spark the deployment of Pi-3-kinase or Mek inhibitors in KRAS-mutant lung tumor patients.