PO.ET01.04 · 实验与分子治疗
葡萄糖条件影响不同种族三阴性乳腺癌中CAMKK2靶向治疗的敏感性
Glucose conditions influence CAMKK2-targeted therapy sensitivity in triple-negative breast cancer of different ancestry
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摘要 Abstract
中文摘要
背景：三阴性乳腺癌（TNBC）与患有特定代谢合并症（包括肥胖、糖尿病和血脂异常）的女性中较高的发病率和死亡率相关。钙/钙调蛋白依赖性蛋白激酶激酶2（CAMKK2）是调节TNBC细胞中细胞能量代谢和应激适应的核心激酶。本研究考察不同葡萄糖条件如何影响TNBC细胞系的存活及其对CAMKK2抑制剂的反应。
方法：将一组常用的TNBC细胞系（MDA MB 231、MDA MB 468、MDA MB 157、HCC1806）在不同葡萄糖水平下用STO 609和SGC CAMKK2 1处理。细胞在四种葡萄糖条件下孵育：0.33 mM（重度低血糖）、5 mM（生理/正常）、17.5 mM（中度高血糖）和50 mM（极度高血糖）。在这些条件下药物处理后评估IC₅₀值和细胞活力。
结果与结论：在所有细胞系中，结果表明当葡萄糖水平从中等（5、17.5 mM）变为低（0.33 mM）或高（50 mM）时，IC₅₀总体升高（抑制剂敏感性降低）。对于STO-609，IC₅₀值从0.33 mM时的71-2533 µM改善至17.5 mM时的32-91 µM，但在50 mM时再次升高至92-894 µM。对于SGC-CAMKK2-1，IC₅₀从0.33 mM时的112-619 µM至17.5 mM时的48-148 µM，并在50 mM时再次升高至154-520 µM。值得注意的是，HCC1806细胞对两种CAMKK2抑制剂最敏感，而MDA MB 157总体上更耐药。不同的葡萄糖条件对CAMKK2靶向抑制剂在TNBC中的疗效有显著影响，一些细胞系表现出更强的代谢敏感性。这些发现表明，考虑代谢背景的个性化治疗策略可能改善侵袭性乳腺癌的治疗结局。
查看英文原文 English abstract
Background: Triple-negative breast cancer (TNBC) is associated with a higher incidence and mortality in women with specific metabolic comorbidities, including obesity, diabetes, and dyslipidemia. Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) is a central kinase regulating cellular energy metabolism and stress adaptation in TNBC cells. This study examines how different glucose conditions affect the survival and response of TNBC cell lines to CAMKK2 inhibitors.
Methods: A panel of commonly used TNBC cell lines (MDA MB 231, MDA MB 468, MDA MB 157, HCC1806) were treated with STO 609 and SGC CAMKK2 1 at various glucose levels. Cells were incubated under four glucose conditions, 0.33 mM (severe hypoglycemia), 5 mM (physiological/normal), 17.5 mM (moderate hyperglycemia), and 50 mM (extreme hyperglycemia). IC₅₀ values and cell viability were assessed following drug treatment across these conditions.
Results and Conclusion: In all cell lines, results indicated an overall increase in IC₅₀ (reduced inhibitor sensitivity) as glucose levels changed from moderate (5, 17.5 mM) to either low (0.33 mM) or high (50 mM). For STO-609, IC₅₀ values improved from 71-2533 µM at 0.33 mM to 32-91 µM at 17.5 mM but increased again to 92-894 µM at 50 mM. With SGC-CAMKK2-1, IC₅₀ ranged from 112-619 µM at 0.33 mM to 48-148 µM at 17.5 mM and increased again to 154-520 µM at 50 mM. Notably, HCC1806 cells were the most sensitive to both CAMKK2 inhibitors, while MDA MB 157 was overall more resistant. Different glucose conditions have a significant impact on the efficacy of CAMKK2-targeted inhibitors in TNBC, with some cell lines displaying more metabolic sensitivity than others. These findings demonstrate that personalized therapeutic strategies, considering the metabolic background, may improve treatment outcomes in aggressive breast cancers.
利益披露 Disclosure
E. Amini, None..
S. Aramgam, None..
K. Webb, None..
S. Kimbro, None.