ActivatingKRASmutations are major oncogenic drivers in multiple tumor types. Synthetic lethal screens have previously been used to identify targets critical for the survival ofKRASmutant cells, but their application to drug discovery has proven challenging, possibly due in part to a failure of monolayer cultures to model tumor biology. Here, we report the results of a high-throughput synthetic lethal screen for small molecules that selectively inhibit the growth ofKRASmutant cell lines in soft agar. Chemoproteomic profiling identifies the target of the mostKRAS-selective chemical series as dihydroorotate dehydrogenase (DHODH). DHODH inhibition is shown to perturb multiple metabolic pathways.In vivopreclinical studies demonstrate strong antitumor activity upon DHODH inhibition in a pancreatic tumor xenograft model.

中文翻译：

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对嘧啶生物合成酶DHODH的依赖是突变的KRAS驱动的癌症中的合成致死性脆弱性。

激活KRAS突变是多种肿瘤类型中的主要致癌驱动因素。合成致死筛选以前曾用于鉴定对KRAS突变细胞的生存至关重要的靶标，但事实证明，将其应用于药物发现具有挑战性，这可能部分是由于单层培养物无法建立肿瘤生物学模型所致。在这里，我们报告高通量合成致命筛选的小分子，选择性抑制软琼脂中KRAS突变细胞系生长的结果。化学计量学分析将大多数KRAS选择性化学系列的目标确定为二氢乳清酸脱氢酶（DHODH）。DHODH抑制作用可干扰多种代谢途径。体内临床前研究表明，在胰腺肿瘤异种移植模型中，DHODH抑制作用具有很强的抗肿瘤活性。