PO.ET03.02 · 实验与分子治疗
PASK（Per-Arnt-Sim激酶）抑制剂在可变葡萄糖条件下对三阴性乳腺癌疗效的血统依赖性差异
Ancestry-dependent differences of PASK (Per-Arnt-Sim Kinase) inhibitor efficacy in triple-negative breast cancer under variable glucose conditions
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
非裔美国女性的乳腺癌死亡率比欧洲血统女性高近40%。造成这一结果的一个主要因素是三阴性乳腺癌（TNBC），它不成比例地影响非裔美国女性，并与更具侵袭性的疾病相关。Per-Arnt-Sim激酶（PASK）是一种营养敏感性蛋白激酶，调控葡萄糖和脂质代谢。既往研究表明，PASK通过多条代谢和信号通路促进肿瘤生长，在乳腺癌进展中发挥重要作用。初步证据提示，PASK抑制剂BioE-1115在不同血统背景的TNBC细胞系中、在不同葡萄糖水平下表现出差异性疗效。代表非洲血统（HCC-1806和MDA-MB-468）和欧洲血统（MDA-MB-231）的TNBC细胞系被培养于含生理相关葡萄糖浓度的培养基中，分别代表低血糖（2.5 mM；45 mg/dL）、正常血糖（5.5 mM；100 mg/dL）、高血糖（11 mM；198 mg/dL）和重度高血糖（17.5 mM；315.1 mg/dL）。在BioE-1115处理后进行细胞活力实验，以量化对该抑制剂反应中血统依赖性和葡萄糖依赖性差异。为每种条件计算半数最大抑制浓度（IC₅₀）值。BioE-1115在各TNBC细胞系中表现出不同的疗效特征。非洲血统的HCC-1806和MDA-MB-468细胞对BioE-1115的敏感性显著降低，在等效葡萄糖条件下其IC₅₀值比欧洲血统的MDA-MB-231细胞高1.3至1.5倍。在不同葡萄糖浓度下观察到抑制剂反应的变异性，表明代谢状态可改变PASK抑制剂的疗效。PASK抑制初步提示治疗反应存在血统依赖性差异，且这种差异进一步受葡萄糖可用性的调节。这些发现强调了在评估针对TNBC的靶向代谢疗法时整合血统相关遗传和代谢背景的重要性。这项工作提供了基础性数据，支持需要采用同时考虑血统相关生物学和代谢应激的精准肿瘤学方法。
查看英文原文 English abstract
Breast cancer mortality rates are nearly 40% higher in African American women than in women of European ancestry. A major contributor to this outcome is triple-negative breast cancer (TNBC), which disproportionately affects African American women and is associated with more aggressive disease. Per-Arnt-Sim Kinase (PASK) is a nutrient-sensitive protein kinase that regulates glucose and lipid metabolism. Previous studies have shown that PASK plays a significant role in breast cancer progression by promoting tumor growth through several metabolic and signaling pathways. Preliminary evidence suggests that the PASK inhibitor, BioE-1115, exhibits differential efficacy across TNBC cell lines of distinct ancestral backgrounds across varying glucose levels. TNBC cell lines representing African ancestry (HCC-1806 and MDA-MB-468) and European ancestry (MDA-MB-231) were cultured in media containing physiologically relevant glucose concentrations representing hypoglycemia (2.5 mM; 45 mg/dL), normoglycemia (5.5 mM; 100 mg/dL), hyperglycemia (11 mM; 198 mg/dL), and severe hyperglycemia (17.5 mM; 315.1 mg/dL). Cell viability assays were performed following BioE-1115 treatment to quantify ancestry- and glucose-dependent differences in the response to the inhibitor. Half-maximal inhibitory concentration (IC₅₀) values were calculated for each condition. BioE-1115 demonstrated distinct efficacy profiles across TNBC cell lines. The African-ancestry HCC-1806 and MDA-MB-468 cells displayed markedly reduced sensitivity to BioE-1115, with IC₅₀ values 1.3x-1.5x higher compared with the European-ancestry MDA-MB-231 cells under equivalent glucose conditions. Variability in inhibitor response was observed across glucose concentrations, indicating that metabolic state modifies PASK inhibitor efficacy. PASK inhibition preliminarily suggests ancestry-dependent differences in therapeutic response that are further modulated by glucose availability. These findings highlight the importance of integrating ancestry-informed genetic and metabolic context when evaluating targeted metabolic therapies for TNBC. This work provides foundational data supporting the need for precision-oncology approaches that consider both ancestry-linked biology and metabolic stressors.
利益披露 Disclosure
A. Olayiwola, None..
S. Aramgam, None.