Synthetic lethality in the context of chromosome 8p deletion in liver cancer

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Tumorigenesis involves oncogene activation and tumor suppressor gene (TSG) loss leading to dereg-ulation of cellular signaling. These alterations are thought to create dependencies of cancer cells. Knowledge of these synthetic lethal interactions will enable us to specifically treat tumors while leaving non-tumor cells unaffected. Chromosome 8p deletion is one of the most common lesions in epithelial tumors, such as HCC and multiple TSGs have been reported within this region. Current screens for synthetic lethal interactions were performed using RNAi or chemical compounds in tumor cell lines comparing oncogene activation to normal cells. Despite their technical innovation and importance for our understanding of vulnerabilities of Ras-dependent cancer cells, these screens might underestimate targets due to a lack of relevant physiological signaling in their systems. Therefore, I want to establish a mouse “mosaic” liver cancer model resembling chromosome 8p deletion to investigate vulnerabilities in a physiological context. Short hairpin RNAs targeting 8p TSGs will sensitize liver progenitor cells (LPCs) to malignant transformation and serve as model system. These LPCs will be used to identify synthetic lethal interactions of tumors with 8p deletions in vivo by applying regulateable RNAi targeting ~1000 cancer-signaling genes for which pharmacological inhibitors are available to combine genetic screening with compound validation. Subsequently, tumors will be treated with corresponding inhibitors to confirm applicability of the identified genes. In addition, human HCC cells with 8p deletions will be genetically and pharmacologically tested for their susceptibility to the inhibition of these genes. Furthermore, the underlying signaling pathways will be delineated to improve our understanding of tumor signaling networks. This study will enable us to reveal vulnerabilities of 8p-dependent liver tumors helping to identify novel drug targets for the treatment of HCC.