Combination therapies induce cancer cell death through the integrated stress response and disturbed pyrimidine metabolism

By accentuating drug efficacy and impeding resistance mechanisms, combinatorial, multi-agent therapies have emerged as key approaches in the treatment of complex diseases, most notably cancer. Using high-throughput drug screens, we uncovered distinct metabolic vulnerabilities and thereby identified drug combinations synergistically causing a starvation-like lethal catabolic response in tumor cells from different cancer entities. Domperidone, a dopamine receptor antagonist, as well as several tricyclic antidepressants (TCAs), including Imipramine, induced cancer cell death in combination with the mitochondrial uncoupler Niclosamide ethanolamine (NEN) through activation of the integrated stress response pathway and the catabolic CLEAR network. Using transcriptome and metabolome analyses, we characterized a combinatorial response, mainly driven by the transcription factors Chop and TFE3, which resulted in cell death damage through enhanced pyrimidine catabolism as well as reduced pyrimidine synthesis. Remarkably, the drug combinations sensitized human organoid cultures to the standard-of-care chemotherapy Paclitaxel. Thus, our combinatorial approach could be clinically implemented into established treatment regimen, which would be further facilitated by the advantages of drug repurposing.

通过强化药物疗效并阻断耐药机制，联合多药剂疗法已成为复杂疾病（尤以癌症为代表）治疗的核心策略。本研究借助高通量药物筛选技术，揭示了肿瘤细胞独特的代谢脆弱性，并据此筛选出可在不同癌种的肿瘤细胞中协同引发类似饥饿状态的致死性分解代谢反应的药物组合。多巴胺受体拮抗剂多潘立酮，以及包括丙米嗪在内的数种三环类抗抑郁药（TCAs），可与线粒体解偶联剂氯硝柳胺乙醇胺盐（NEN）联用，通过激活整合应激反应通路与分解代谢CLEAR网络诱导肿瘤细胞死亡。通过转录组与代谢组分析，我们对该联合疗法的应答特征进行了表征：该应答主要由转录因子Chop与TFE3驱动，通过增强嘧啶分解代谢并抑制嘧啶合成，最终引发细胞致死性损伤。值得注意的是，该药物组合可使人类类器官培养物对临床标准化疗药物紫杉醇增敏。综上，本研究提出的联合疗法可纳入现有临床治疗方案，而药物重定位的优势将进一步推动该疗法的临床转化与应用。