索托拉西布获得性耐药肺癌细胞的代谢轮廓分析

doi:10.3969/j.issn.1674-8115.2025.02.002

上海交通大学学报（医学版） ›› 2025, Vol. 45 ›› Issue (2): 138-149.doi: 10.3969/j.issn.1674-8115.2025.02.002

• 论著 · 基础研究 • 上一篇

索托拉西布获得性耐药肺癌细胞的代谢轮廓分析

邹沛辰¹(), 刘鸿宇², 阿衣娜扎尔·艾合买提¹, 朱亮¹, 唐亚斌¹(), 雷绘敏¹()

^1.上海交通大学基础医学院药理学与化学生物学系，上海 200025
^2.上海交通大学医学院附属胸科医院呼吸内科，上海 200030

收稿日期:2024-07-09 接受日期:2024-10-23 出版日期:2025-02-28 发布日期:2025-02-28
通讯作者: 唐亚斌,雷绘敏 E-mail:peichenzou1997@163.com;leonyabin2018@shsmu.edu.cn;leihuimin02@163.com
作者简介:邹沛辰（1997—），男，硕士生；电子信箱：peichenzou1997@163.com。
基金资助:
国家自然科学基金项目(82273950);上海市自然科学基金(21ZR1436700)

Metabolic profiling of lung cancer cells with acquired resistance to sotorasib

ZOU Peichen¹(), LIU Hongyu², AIHEMAITI· Ayinazhaer¹, ZHU Liang¹, TANG Yabin¹(), LEI Huimin¹()

^1.Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University College of Basic Medical Sciences, Shanghai 200025, China
^2.Department of Pulmonary Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China

Received:2024-07-09 Accepted:2024-10-23 Online:2025-02-28 Published:2025-02-28
Contact: TANG Yabin, LEI Huimin E-mail:peichenzou1997@163.com;leonyabin2018@shsmu.edu.cn;leihuimin02@163.com
Supported by:
National Natural Science Foundation of China(82273950);Natural Science Foundation of Shanghai(21ZR1436700)

摘要/Abstract

摘要：

目的·探究KRAS靶向抑制剂索托拉西布（sotorasib）获得性耐药肺癌细胞的代谢特征及代谢重编程规律。方法·构建肺癌细胞H2122和H358的索托拉西布获得性耐药细胞模型（H2122-SR和H358-SR细胞），并采用CCK-8法加以验证。应用超高效液相色谱串联四极杆飞行时间质谱（UPLC-QTOF/MS）分析获得性耐药肺癌细胞及其同源亲本细胞的代谢轮廓，利用主成分分析法和偏最小二乘法-判别分析法等统计学方法进行非靶向代谢组学分析及代谢表征，筛选并鉴定索托拉西布获得性耐药相关的差异代谢物，并对所筛选到的差异代谢物进行通路富集分析。通过绘制热图比较分析主要差异代谢通路上的代谢物在耐药细胞与亲本细胞之间的差异。结果·成功构建H2122和H358细胞的获得性耐药细胞模型，对索托拉西布的半数抑制浓度均较亲本细胞提升50倍以上。与亲本细胞相比，耐药细胞代谢轮廓存在显著差异。H2122-SR与H2122细胞之间发现48种差异代谢物，其中变量投影重要程度（variable importance in the projection，VIP）值排名前10位的差异代谢物为尿嘧啶、黄苷酸、吲哚-3-甲酸、烟酸、黄苷、黄嘌呤、N-甲基烟酰胺、次黄嘌呤、葫芦巴碱、半乳糖醛酸；H358-SR与H358细胞之间发现79种差异代谢物，其中VIP值排名前10位的差异代谢物为还原型谷胱甘肽、黄苷、α-酮戊二酸、羧甲基赖氨酸、胸苷、嘌呤、核黄素、3-吲哚丙烯酸、吲哚-3-丙酮酸、二氢尿嘧啶。2种肺癌细胞系的差异代谢通路主要涉及嘌呤代谢和糖酵解/糖异生，其中嘌呤代谢变化最为显著。热图分析显示，耐药细胞嘌呤代谢途径多数代谢物水平升高。结论·索托拉西布获得性耐药的肺癌细胞嘌呤代谢增强。

关键词: 肺癌, 索托拉西布, 耐药性, 代谢轮廓, 超高效液相色谱串联高分辨质谱, 嘌呤代谢

Abstract:

Objective ·To explore the metabolic profiling and metabolic reprogramming patterns of lung cancer cells with acquired resistance to sotorasib, a specific inhibitor to KRAS. Methods ·The H2122 and H358 lung cancer cell models with acquired resistance to sotorasib (H2122-SR and H358-SR cells) were established and validated by CCK-8 assay. Ultra-performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) was employed to acquire the metabolic profiling of the resistant lung cancer cells and their homologous parental cells. Untargeted metabolomics studies and metabolic characterizations were conducted with multi-dimensional methods, including principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA), to identify differential metabolites associated with acquired resistance to sotorasib. Then these differential metabolites were subjected to pathway enrichment analysis. Heatmap analysis was used to compare the changes in metabolites in major differential metabolic pathways between the resistant and parental cells. Results ·The cell models of H2122 and H358 with acquired resistance were successfully constructed, with half-maximal inhibitory concentrations (IC₅₀) of sotorasib being 50 times higher than those of the parental cells. Besides, the metabolic profiling was significantly different between the resistant and parental cells. A total of 48 differential metabolites were identified between H2122-SR and H2122 cells. The top 10 differential metabolites, ranked by VIP values, were uridine, xanthylic acid, indole-3-carboxylic acid, nicotinic acid, xanthosine, xanthine, N-methylnicotinamide, hypoxanthine, trigonelline, and galactonic acid. Between H358-SR and H358 cells, a total of 79 differential metabolites were identified. The top 10 differential metabolites, ranked by VIP values, were glutathione, xanthosine, 2-ketoglutaric acid, carboxyethyl lysine, thymidine, purine, riboflavin, 3-indoleacrylic acid, indole-3-pyruvic acid, and dihydrouracil. The differential metabolites in the two lung cancer cell lines mainly participated in purine metabolism and glycolysis/gluconeogenesis, and purine metabolism was the most significantly altered metabolic pathway. Heatmap analysis showed that many metabolites in the purine metabolism were elevated in the sotorasib-resistant cells. Conclusion ·The lung cancer cells with acquired resistance to sotorasib show enhanced purine metabolism.

Key words: lung cancer, sotorasib, drug resistance, metabolic profiling, ultra-performance liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS), purine metabolism

中图分类号:

R734.2

邹沛辰, 刘鸿宇, 阿衣娜扎尔·艾合买提, 朱亮, 唐亚斌, 雷绘敏. 索托拉西布获得性耐药肺癌细胞的代谢轮廓分析[J]. 上海交通大学学报（医学版）, 2025, 45(2): 138-149.

ZOU Peichen, LIU Hongyu, AIHEMAITI· Ayinazhaer, ZHU Liang, TANG Yabin, LEI Huimin. Metabolic profiling of lung cancer cells with acquired resistance to sotorasib[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2025, 45(2): 138-149.

图/表 12

表1 H2122-SR和H2122细胞样本的梯度洗脱程序

Tab 1 Gradient elution program for H2122-SR and H2122 cells

Time/min	Flow rate/ (mL·min^-1)	Mobile phase A/%	Mobile phase B/%
0	0.25	10	90
1.5	0.25	10	90
20	0.25	60	40
25	0.25	60	40
25.01	0.25	10	90
33	0.25	10	90

表2 H358-SR和H358细胞样本的梯度洗脱程序

Tab 2 Gradient elution program for H358-SR and H358 cells

Time/min	Flow rate/ (mL·min^-1)	Mobile phase A/%	Mobile phase B/%
0	0.5	5	95
0.5	0.5	5	95
7	0.5	35	65
8	0.5	60	40
9	0.5	60	40
9.01	0.5	5	95
12	0.5	5	95

图1 索托拉西布耐药肺癌细胞模型的鉴定Note： The cells were treated with indicated concentrations of sotorasib for 72 h. The viability of sotorasib-resistant cells H2122-SR and H358-SR and their corresponding parental cells H2122 and H358 were analyzed by CCK-8 assay. A. H2122 and H2122-SR cells. B. H358 and H358-SR cells.

Fig 1 Identification of sotorasib-resistant cell models in lung cancer

图2 H2122和H2122-SR细胞代谢总离子流色谱图Note： A. Representative chromatogram of H2122 cells in ESI+. B. Representative chromatogram of H2122-SR cells in ESI+. C. Representative chromatogram of H2122 cells in ESI-. D. Representative chromatogram of H2122-SR cells in ESI-. cps—counts per second.

Fig 2 Representative chromatograms of H2122 and H2122-SR cells in ESI

图3 H358和H358-SR细胞代谢总离子流色谱图Note： A. Representative chromatogram of H358 cells in ESI+. B. Representative chromatogram of H358-SR cells in ESI+. C. Representative chromatogram of H358 cells in ESI-. D. Representative chromatogram of H358-SR cells in ESI-.

Fig 3 Representative chromatograms of H358 and H358-SR cells in ESI

图4 H2122-SR和H358-SR细胞与其亲本细胞的PCA得分图Note： A/B. PCA score plots of H2122-SR (A, n=6) and H358-SR (B, n=5) with their corresponding parental cells in ESI+. C/D. PCA score plots of H2122-SR (C, n=6) and H358-SR (D, n=5) with their corresponding parental cells in ESI-. Green circles represent parental cells, and red circles represent SR cells.

Fig 4 PCA score plots of H2122-SR and H358-SR cells with their parental cells

图5 H2122-SR和H358-SR细胞与其亲本细胞的PLS-DA得分图Note： A/B. PLS-DA score plots of H2122-SR (A, n=6) and H358-SR (B, n=5) with their corresponding parental cells in ESI+. C/D. PLS-DA score plots of H2122-SR (C, n=6) and H358-SR (D, n=5) with their corresponding parental cells in ESI-. Green circles represent parental cells, and red circles represent SR cells.

Fig 5 PLS-DA score plots of H2122-SR and H358-SR cells with their parental cells

表3 H2122-SR与H2122细胞VIP排序前10位的差异代谢物

Tab 3 Top 10 differential metabolites in VIP ranking between H2122-SR and H2122 cells

No.	Name	VIP	FC (SR/Par)	P value	Score
1	Uridine	4.17	0.005	9.16×10^-6	94
2	Xanthylic acid	3.02	25.748	1.19×10^-5	96
3	Indole-3-carboxylic acid	2.80	18.718	7.79×10^-8	100
4	Nicotinic acid	2.77	18.143	2.04×10^-8	98
5	Xanthosine	2.42	8.841	2.17×10^-6	93
6	Xanthine	2.29	7.136	2.48×10^-6	99
7	N-methylnicotinamide	2.20	0.161	3.94×10^-9	99
8	Hypoxanthine	2.14	5.898	3.33×10^-6	99
9	Trigonelline	2.06	5.809	3.08×10^-5	90
10	Galactonic acid	2.04	0.451	1.74×10^-4	90

表4 H358-SR与H358细胞VIP排序前10位的差异代谢物

Tab 4 Top 10 differential metabolites in VIP ranking between H358-SR and H358 cells

No.	Name	VIP	FC (SR/Par)	P value	Score
1	Glutathione	2.31	38.656	3.43×10^-5	92
2	Xanthosine	2.25	31.638	4.47×10^-7	85
3	2-Ketoglutaric acid	2.21	25.561	1.64×10^-4	99
4	Carboxyethyl lysine	2.11	38.608	3.73×10^-4	90
5	Thymidine	2.10	0.036	1.05×10^-4	85
6	Purine	2.05	18.272	3.43×10^-5	90
7	Riboflavin	1.99	15.114	1.01×10^-6	92
8	3-Indolylacrylic acid	1.98	45.888	1.38×10^-4	85
9	Indole-3-pyruvic acid	1.82	0.439	5.32×10^-5	85
10	Dihydrouracil	1.79	15.319	6.22×10^-7	100

图6 H2122-SR和H2122细胞的差异代谢通路富集分析Note： TCA cycle—tricarboxylic acid cycle.

Fig 6 Differential metabolic pathway enrichment analysis between H2122-SR and H2122 cells

图7 H358-SR和H358细胞的差异代谢通路富集分析

Fig 7 Differential metabolic pathway enrichment analysis between H358-SR and H358 cells

图8 H2122-SR和H358-SR细胞与其亲本细胞的嘌呤代谢物热图分析Note： A. H2122 and H2122-SR cells. B. H358 and H358-SR cells. Red represents upregulation, and blue represents downregulation. R5P—ribose-5-phosphate; PRPP—phosphoribosyl pyrophosphate; IMP—inosine monophosphate; AMP—adenosine monophosphate; GMP—guanosine monophosphate.

Fig 8 Heatmap analysis of purine metabolites of H2122-SR and H358-SR cells with their parental cells

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索托拉西布获得性耐药肺癌细胞的代谢轮廓分析

Metabolic profiling of lung cancer cells with acquired resistance to sotorasib

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