Genomic alterations were found to cause the inactivation of the tumour suppressor Adenomatous polyposis coli (APC) genes in more than 80% of colon cancers. Although there is clear evidence demonstrating the importance of APC in colon cancer pathogenesis, we still lack approaches for direct targeting of tumour suppressors. However, previous studies created a new window to identify a class of genetic vulnerabilities that are associated with DNA loss of a tumour suppressor termed CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial loss). Most notably, SRP19, which is a component of the signal recognition particle complex, has been identified as a CYCLOPS. The primary objective of this study is to evaluate SRP19 as a therapeutic target and to develop strategies to inhibit SRP19 to treat colon cancer.
Initially we found APCLoss cancers have lower level of the mRNA and protein of SRP19, and siRNAs targeting SRP19 were used, which showed that APCLoss cancers are highly sensitive to further suppression of SRP19. Our preliminary data showed that other components of SRP complex are well correlated with SRP19, hence we will evaluate the abundance and activity of SRP complex in WT or cells with partial SRP19 loss by using native gel electrophoresis. Furthermore, we will also measure the effect of SRP19 loss on the ability of the SRP complex to translocate proteins across the ER membrane.
This project will identify inhibitors of SRP19 activity as a component of SRP complex, and test the inhibitors of SRP19 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.