传统培养基中的非生理营养水平已被证明会影响癌细胞在多个方面的生理机能，包括细胞对某些治疗药物的反应。在本研究中，我们通过在人血浆样介质（HPLM）中进行药物筛选全面评估了生理营养水平对治疗反应的影响。我们观察到营养水平对多种FDA批准和临床试验化合物的敏感性产生了显著的营养依赖性变化，包括最近在第三阶段临床试验中失败的实验性抗癌药物rigosertib。从机理上讲，我们发现嘌呤代谢废物尿酸可以强烈抑制rigosertib破坏微管的能力，尿酸在人体中相对于传统的体外和体内癌症模型更为丰富。结构建模研究表明，尿酸与tubulin-rigosertib复合物发生相互作用，并可能作为rigosertib的非竞争性抑制剂。这些结果为rigosertib在临床试验中的失败提供了可能的解释，并证明了生理培养基在实现更符合人类治疗反应的体外结果方面的实用性。

The non-physiological nutrient levels found in traditional culture media have been shown to affect numerous aspects of cancer cell physiology, including how cells respond to certain therapeutic agents. Here, we comprehensively evaluated how physiological nutrient levels impact therapeutic response by performing drug screening in human plasma-like medium (HPLM). We observed dramatic nutrient-dependent changes in sensitivity to a variety of FDA-approved and clinically trialed compounds, including rigosertib, an experimental cancer therapeutic that has recently failed in phase 3 clinical trials. Mechanistically, we found that the ability of rigosertib to destabilize microtubules is strongly inhibited by the purine metabolism waste product uric acid, which is uniquely abundant in humans relative to traditional in vitro and in vivo cancer models. Structural modelling studies suggest that uric acid interacts with the tubulin-rigosertib complex and may act as an uncompetitive inhibitor of rigosertib. These results offer a possible explanation for the failure of rigosertib in clinical trials and demonstrate the utility of physiological media to achieve in vitro results that better represent human therapeutic responses.