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.
Initially we found APC loss cancers have lower level of the mRNA and protein of SRP19, and siRNAs targeting SRP19 were used, which showed that APC loss cancers are highly sensitive to further suppression of SRP19. We have validated that with rescue experiments and in xenograft mouse model. The copy number loss of APC results in the partial loss of nearby SRP19, which also affects other parts of the SRP complex including SRP54. SRP54 is the most important functional component of the SRP complex, which were also found to be more dependent in APC loss cancers. We also validated that not only SRP19, but also the entire SRP complex and the protein secretion machinery, are vulnerabilities in cancers with APC copy number loss. Importantly, the same approach could also be used for identifying and targeting any other cancers harbouring partial loss of a tumour suppressor.