Chemical screens across hundreds of cell lines have shown that the drug sensitivities of human cancers can vary by genotype or lineage. However, most drug discovery studies have relied on culture media that poorly reflect metabolite levels in human blood. Here, we perform drug screens in traditional and Human Plasma–Like Medium (HPLM). Sets of compounds that show conditional anticancer activity span different phases of global development and include non-oncology drugs. Comparisons of the synthetic and serum-derived components that comprise typical media trace sets of conditional phenotypes to nucleotide synthesis substrates. We also characterize a unique dual mechanism for brivudine, a compound approved for antiviral use. Brivudine selectively impairs cell growth in low folate conditions by targeting two enzymes involved in one-carbon metabolism. Cataloged gene essentiality data further suggest that conditional phenotypes for other compounds are linked to off-target effects. Our findings establish general strategies for identifying drug-nutrient interactions and mechanisms of action by exploiting conditional lethality in cancer cells.

中文翻译：

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条件致死性分析揭示了抗癌作用机制和药物-营养相互作用


对数百种细胞系的化学筛选表明，人类癌症的药物敏感性可能因基因型或谱系而异。然而，大多数药物发现研究所依赖的培养基不能很好地反映人体血液中的代谢物水平。在这里，我们在传统和人血浆样培养基 （HPLM） 中进行药物筛选。显示条件性抗癌活性的化合物集跨越了全球开发的不同阶段，包括非肿瘤药物。合成和血清衍生成分的比较，这些成分构成了典型的培养基痕量条件表型集到核苷酸合成底物。我们还表征了布夫定的独特双重机制，布夫定是一种被批准用于抗病毒的化合物。布夫定通过靶向参与一碳代谢的两种酶，选择性地损害低叶酸条件下的细胞生长。编目的基因必要性数据进一步表明，其他化合物的条件表型与脱靶效应有关。我们的研究结果通过利用癌细胞中的条件致死性，建立了识别药物-营养相互作用和作用机制的一般策略。