Mapping Novel Metabolic Nodes Targeted by Anti-Cancer Drugs that Impair Triple-Negative Breast Cancer Pathogenicity

Triple-negative breast cancers (TNBCs)
are estrogen receptor, progesterone receptor, and HER2 receptor-negative
subtypes of breast cancers that show the worst prognoses and lack
targeted therapies. Here, we have coupled the screening of ∼400
anticancer agents that are under development or in the clinic with
chemoproteomic and metabolomic profiling to identify novel metabolic
mechanisms for agents that impair TNBC pathogenicity. We identify
20 anticancer compounds that significantly impaired cell survival
across multiple types of TNBC cells. Among these 20 leads, the phytoestrogenic
natural product licochalcone A was of interest, since TNBCs are unresponsive
to estrogenic therapies, indicating that licochalcone A was likely
acting through another target. Using chemoproteomic profiling approaches,
we reveal that licochalcone A impairs TNBC pathogenicity, not through
modulating estrogen receptor activity but rather through inhibiting
prostaglandin reductase 1, a metabolic enzyme involved in leukotriene
B4 inactivation. We also more broadly performed metabolomic profiling
to map additional metabolic mechanisms of compounds that impair TNBC
pathogenicity. Overlaying lipidomic profiling with drug responses,
we find that deubiquitinase inhibitors cause dramatic elevations in
acyl carnitine levels, which impair mitochondrial respiration and
contribute to TNBC pathogenic impairments. We thus put forth two unique
metabolic nodes that are targeted by drugs or drug candidates that
impair TNBC pathogenicity. Our results also showcase the utility of
coupling drug screens with chemoproteomic and metabolomic profiling
to uncover unique metabolic drivers of TNBC pathogenicity.

三阴性乳腺癌（Triple-negative breast cancers, TNBCs）是雌激素受体、孕激素受体及人表皮生长因子受体2（HER2）均呈阴性的乳腺癌亚型，其预后最差且缺乏靶向治疗手段。本研究将针对约400种在研或临床在用的抗肿瘤药物的筛选，与化学蛋白质组学、代谢组学分析相结合，旨在揭示能够削弱三阴性乳腺癌致病能力的药物的新型代谢机制。我们筛选得到20种可显著抑制多种三阴性乳腺癌细胞存活的抗肿瘤化合物。在这20种候选化合物中，植物雌激素类天然产物甘草查尔酮A（licochalcone A）引起了我们的关注：由于三阴性乳腺癌对雌激素疗法无应答，提示甘草查尔酮A的作用机制可能并非通过雌激素通路。借助化学蛋白质组学分析手段，我们发现甘草查尔酮A并非通过调控雌激素受体活性，而是通过抑制前列腺素还原酶1——一种参与白三烯B4灭活的代谢酶——来削弱三阴性乳腺癌的致病能力。此外，我们还开展了更广泛的代谢组学分析，以绘制其他可削弱三阴性乳腺癌致病能力的化合物的代谢作用机制图谱。将脂质组学分析结果与药物响应数据进行整合后，我们发现去泛素化酶抑制剂可显著升高酰基肉碱水平，该过程会损伤线粒体呼吸功能，并参与削弱三阴性乳腺癌的致病能力。综上，本研究明确了两类可被削弱三阴性乳腺癌致病能力的药物/候选药物靶向的独特代谢节点。本研究结果同时证实，将药物筛选与化学蛋白质组学、代谢组学分析相结合的策略，可有效揭示三阴性乳腺癌致病能力的新型代谢驱动因素。