Genomic alterations leading to inactivation of the tumour suppressor Adenomatous polyposis coli (APC) genes are found in more than 80% of colon cancers. However, we still lack approaches for direct targeting of APC. As an alternative approach for direct targeting of a tumour suppressor gene we used RNAi based genome wide screens to identify genes that are required in a subset of cancers with hemizygous APC deletion (20% of colon cancers). We found that SRP19, a cell essential protein that is part of the SRP complex, is essential for proliferation of these cancers. Specifically, due to their close physical proximity one allele of SRP19 is lost as a consequence of APC loss. This leads to lower SRP19 mRNA and protein levels in APCLoss cancers and results in high sensitivity to additional suppression of SRP19. This phenomenon of passenger dependencies is termed CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial loss) and results in a new type of cancer targets.
Our results show validation of SRP19 as a target in APCLoss cancers. We found APCLoss cancers have lower level of the mRNA and protein of SRP19, and siRNAs targeting SRP19 shows that APCLoss cancers are highly sensitive to further suppression of SRP19. Furthermore, we demonstrate that other components of SRP complex are well correlated with SRP19, demonstrating the SRP complex as a vulnerability in APCLoss cancers.
This project will identify inhibitors of SRP19 activity as a component of SRP complex, and test them in animal models, which will provide us a new approach for treatment of colon cancers harbouring APC loss. Moreover, although this project is aimed at a specific population of APC deleted colon cancer, vulnerability to suppression of CYCLOPS genes could be used for targeting of any heterozygous loss of a tumour suppressor in cancer.