升高的RAS信号在人类癌症中广泛存在，然而使用RAS信号通路抑制剂针对RAS驱动的癌症经常导致不良副作用和药物耐受性。因此，识别与RAS通路抑制剂协同作用的化合物将使低剂量的RAS通路抑制剂得以使用并降低药物耐受性。在这里，我们使用果蝇模型的RAS驱动癌症进行了精选化学药品筛选，发现一些化合物能够通过协同作用减小肿瘤的大小，与亚治疗剂量的RAS通路抑制剂Trametinib一起使用。对其中的一个命中物Ritanserin和相关化合物的分析显示，双酰氨基甘油激酶α（DGKa）是协同Trametinib所需的关键靶标。携带H-RAS癌基因和细胞极性基因SCRIB敲低的人类上皮细胞对Trametinib和DGKa抑制剂治疗也很敏感。机制上，DGKa抑制剂通过提高P38应激反应信号通路在H-RAS SCRIB-RNAi细胞中与Trametinib协同作用，可以导致细胞处于平静状态。我们的研究结果表明，使用RAS通路和DGKa抑制剂针对RAS驱动的人类癌症应该是一种有效的联合药物治疗。©2023。由生物学家有限公司发表。

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.© 2023. Published by The Company of Biologists Ltd.