A Drosophila chemical screen reveals synergistic effect of MEK and DGKalpha inhibition in Ras-driven cancer
- Author(s)
- La Marca, JE; Ely, RW; Diepstraten, ST; Burke, P; Kelly, GL; Humbert, PO; Richardson, HE;
- Details
- Publication Year 2023-03-01,Volume 16,Issue #3,Page dmm049769
- Journal Title
- Disease Models & Mechanisms
- Publication Type
- Research article
- Abstract
- 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 specialised chemical screen using a Drosophila model of Ras-driven cancer, we have identified compounds that reduce tumour size by synergising with sub-therapeutic doses of the Ras pathway inhibitor trametinib, which targets MEK, the mitogen-activated protein kinase kinase, in this pathway. Analysis of one of the hits, ritanserin, and related compounds revealed that diacyl glycerol kinase alpha (DGKalpha, Dgk in Drosophila) 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 were also sensitive to treatment with trametinib and DGKalpha inhibitors. Mechanistically, DGKalpha inhibition synergises with trametinib by increasing the P38 stress-response signalling pathway in H-RASG12V SCRIBRNAi cells, which could lead to cell quiescence. Our results reveal that targeting Ras-driven human cancers with Ras pathway and DGKalpha inhibitors should be an effective combination drug therapy.
- Publisher
- The Company of Biologists
- Keywords
- Animals; Humans; Mitogen-Activated Protein Kinase Kinases; Drosophila; Cell Line, Tumor; Signal Transduction; *Antineoplastic Agents/pharmacology/therapeutic use; Protein Kinase Inhibitors/pharmacology/therapeutic use; *Neoplasms/drug therapy; Ras; scrib; Chemical screening; Diacyl glycerol kinase alpha (DGKalpha); Synergism
- Department(s)
- Laboratory Research
- PubMed ID
- 36861754
- Publisher's Version
- https://doi.org/10.1242/dmm.049769
- Open Access at Publisher's Site
https://doi.org/10.1242/dmm.049769- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2023-07-27 08:03:04
Last Modified: 2023-07-27 08:03:33