Rpl24^Bstmutation suppresses colorectal cancer by promoting eEF2 phosphorylation via eEF2K

Increased protein synthesis supports the rapid proliferation associated with cancer. TheRpl24^Bstmutant mouse reduces the expression of the ribosomal protein RPL24 and has been used to suppress translation and limit tumorigenesis in multiple mouse models of cancer. Here we show thatRpl24^Bstalso suppresses tumorigenesis and proliferation in a model of colorectal cancer with two common patient mutations,ApcandKras. In contrast to previous reports,Rpl24^Bstmutation has no effect on ribosomal subunit abundance but suppresses translation elongation through phosphorylation of eEF2, reducing protein synthesis by 40% in tumour cells. Ablating eEF2 phosphorylation inRpl24^Bstmutant mice by inactivating its kinase, eEF2K, completely restores the rates of elongation and protein synthesis. Furthermore, eEF2K activity is required for theRpl24^Bstmutant to suppress tumorigenesis. This work demonstrates that elevation of eEF2 phosphorylation is an effective means to suppress colorectal tumorigenesis with two driver mutations. This positions translation elongation as a therapeutic target in colorectal cancer, as well as other cancers where theRpl24^Bstmutation has a tumour suppressive effect in mouse models.