Cancer Biology, Oncology Division, Sanofi, Cambridge, MA 02138, USA.
LGCR-LIT, Sanofi, Vitry-Sur-Seine 94400, France.
Cell Chem Biol. 2018 Jun 21;25(6):705-717.e11. doi: 10.1016/j.chembiol.2018.03.005. Epub 2018 Apr 5.
Activating KRAS mutations are major oncogenic drivers in multiple tumor types. Synthetic lethal screens have previously been used to identify targets critical for the survival of KRAS mutant 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 of KRAS mutant cell lines in soft agar. Chemoproteomic profiling identifies the target of the most KRAS-selective chemical series as dihydroorotate dehydrogenase (DHODH). DHODH inhibition is shown to perturb multiple metabolic pathways. In vivo preclinical studies demonstrate strong antitumor activity upon DHODH inhibition in a pancreatic tumor xenograft model.
激活的 KRAS 突变是多种肿瘤类型中的主要致癌驱动因素。之前已经使用合成致死筛选来鉴定对 KRAS 突变细胞存活至关重要的靶点，但它们在药物发现中的应用证明具有挑战性，部分原因可能是单层培养物未能模拟肿瘤生物学。在这里，我们报告了一种高通量的用于小分子的合成致死筛选的结果，这些小分子可以选择性地抑制软琼脂中 KRAS 突变细胞系的生长。化学蛋白质组学分析确定了最具 KRAS 选择性的化学系列的靶标为二氢乳清酸脱氢酶 (DHODH)。DHODH 抑制被证明会扰乱多种代谢途径。在体内临床前研究中，在胰腺肿瘤异种移植模型中抑制 DHODH 表现出强烈的抗肿瘤活性。
