A Drosophila chemical screen reveals targeting MEK and DGKa mitigates Ras-driven polarity-impaired tumour growth.

Elevated RAS signalling is highly prevalent in human cancer, however targeting RAS-driven cancers with RAS-pathway inhibitors often leads to undesirable side-effects and to drug resistance. Thus, identifying compounds that synergise with RAS-pathway inhibitors would enable lower doses of the RAS-pathway inhibitors to be used and also decrease the acquisition of drug resistance. Here, in a boutique chemical screen using a Drosophila model of Ras-driven cancer, we have identified compounds that reduce tumour size by synergising with subtherapeutic doses of the Ras-pathway inhibitor, Trametinib. Analysis of one of the hits, Ritanserin, and related compounds revealed that diacyl glycerol kinase alpha (DGKa) was the critical target required for synergism with Trametinib. Human epithelial cells harbouring the H-RAS oncogene and knockdown of the cell polarity gene, SCRIB, are also sensitive to treatment with Trametinib and DGKa inhibitors. Mechanistically, DGKa inhibition synergises with Trametinib, by increasing the P38 stress-response signalling pathway in H-RAS SCRIB-RNAi cells, which could lead to cell quiescence. Our results reveal that targeting RAS-driven human cancers with RAS-pathway and DGKa inhibitors should be an effective combination drug therapy.