血糖对EGFR突变肺腺癌患者靶向治疗耐药的影响及其机制

doi:10.3969/j.issn.1004-616x.2024.05.005

Abstract

Abstract: OBJECTIVE： To investigate the control of blood glucose factors on efficacy of targeted therapy in patients with epidermal growth factor receptor(EGFR)- mutated lung adenocarcinoma. METHODS： From 2018 to 2019，a total of 277 lung adenocarcinoma patients who received the targeted therapy at the Beijing Chest Hospital，Capital Medical University，were recruited for our study. The relationships among fasting blood glucose (FBG) levels，resistance to targeted therapy and progression-free survival were analyzed. In addition，a culture medium with different glucose concentrations was used to simulate the in vitro glucose environment，and the effects of glucose on the growth of lung adenocarcinoma cell line HCC827 and its derived resistant cell line AZDR were investigated using cell biology methods. According to the glucose content of the cell culture environment，and whether AZD drugs were added or not，four in vitro groups were set up：high glucose，ordinary，high glucose +AZD treatment，and ordinary +AZD treatment groups. Cell proliferation was assessed using colony staining and CCK-8 assays. Cell apoptosis was detected using flow cytometry. Changes in expression of apoptosis-related factors (caspase-3 and metabolism-related protein mTOR) were evaluated using Western blot. RNA sequencing was performed to analyze the gene expression changes in AZDR cells after acquiring resistance. RESULTS： Among patients who showed EGFR-TKI treatment resistance，in addition to the increase of FBG in patients with diabetes combined with lung cancer (37 patients)，FBG in patients with simple lung adenocarcinoma (240 patients) also increased，and 17.4% of lung adenocarcinoma patients exceeded the upper limit of the standard range of FBG in healthy people (6.1 mmol/L). Survival analysis revealed that patients with FBG levels greater than 6.1 mmol/L experienced resistance to targeted therapy later，compared to patients with FBG levels in the range of 4.0-6.0 mmol/L (P<0.05). The cell culture study revealed that the resistant cell line AZDR exhibited slow growth in a high-glucose environment，while the parental cell line HCC827 was not affected. Compared to the parental cell line HCC827，the resistant cell line AZDR showed increased apoptosis rate (P<0.05)，upregulation of apoptosis-related protein caspase-3 (P<0.05)，increased expression of insulin receptor IGFBP7，IGFBP2，IGF1R，and IGF2R，decreased expression of glucose metabolism-related genes SLC16A2，SLC2A13，and HK2，and upregulation of mTOR and HK1 in a high-glucose environment (P<0.05). CONCLUSION： Changes of blood glucose level in patients with lung adenocarcinoma may be an important factor affecting the prognosis and the progression of drug resistance. In vitro studies showed that hyperglycemic environment is not conducive to the survival of drug resistant tumor cell subpopulations，which may be caused by changes in the expression of insulin receptors and glucose metabolism genes. In the process of targeted therapy for lung adenocarcinoma，it may be necessary to dialectically control changes of blood glucose in patients.

Key words: lung adenocarcinoma, fasting blood glucose, targeted therapy, tyrosine kinase inhibitors, tumor resistance

CLC Number:

R734.2

ZHANG Xintong, GU Meng, WANG Ziyu, WEI Panjian, WANG Jinghui, TAN Jinjing. Control of blood glucose on targeted therapy in EGFR-mutated lung adenocarcinoma[J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2024, 36(5): 365-372,383.

References

[1] SUNG H, FERLAY J, SIEGEL R L, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249.
[2] ETTINGER D S, WOOD D E, AGGARWAL C, et al. NCCN guidelines insights: non-small cell lung cancer, version 1.2020[J]. J Natl Compr Canc Netw, 2019, 17(12): 1464-1472.
[3] 中国抗癌协会肿瘤内分泌专业委员会, 重庆市中西医结合学会肿瘤内分泌分会, 周琦, 等. 肿瘤相关性高血糖管理指南(2021年版)[J]. 中国癌症杂志, 2021, 31(7): 651-688.
[4] KÄSMANN L, BOLM L, JANSSEN S, et al. Prognostic factors and treatment of early-stage small-cell lung cancer[J]. Anticancer Res, 2017, 37(3): 1535-1537.
[5] KWAS H, GUERMAZI E, KHATTAB A, et al. Facteurs pronostiques du cancer bronchique non à petites cellules au stade avancé[J]. Rev De Pneumol Clin, 2017, 73(4): 180-187.
[6] GOLDSTRAW P, CHANSKY K, CROWLEY J, et al. The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer[J]. J Thorac Oncol, 2016, 11(1): 39-51.
[7] DETTERBECK F C, BOFFA D J, KIM A W, et al. The eighth edition lung cancer stage classification[J]. Chest, 2017, 151(1): 193-203.
[8] TAN A C, TAN D S W. Targeted therapies for lung cancer patients with oncogenic driver molecular alterations[J]. J Clin Oncol, 2022, 40(6): 611-625.
[9] OH J J, HONG S K, JOO Y M, et al. Impact of sunitinib treatment on blood glucose levels in patients with metastatic renal cell carcinoma[J]. Jpn J Clin Oncol, 2012, 42(4): 314-317.
[10] DINGLI D, WOLF R C, VELLA A. Imatinib and type 2 diabetes[J]. Endocr Pract, 2007, 13(2): 126-130.
[11] CHODOROWSKI Z, SEIN ANAND J, HELLMANN A, et al. No influence of imatinib on type 2 diabetes[J]. Przegl Lek, 2007, 64(4/5): 370-371.
[12] BRECCIA M, MUSCARITOLI M, GENTILINI F, et al. Impaired fasting glucose level as metabolic side effect of nilotinib in non-diabetic chronic myeloid leukemia patients resistant to imatinib[J]. Leuk Res, 2007, 31(12): 1770-1772.
[13] YANG J R, CHEN G C, XU J Y, et al. Fasting blood glucose levels and prognosis in patients with non-small-cell lung cancer: a prospective cohort study in China[J]. Onco Targets Ther, 2019, 12: 5947-5953.
[14] HATLEN P, GR-NBERG B H, LANGHAMMER A, et al. Prolonged survival in patients with lung cancer with diabetes mellitus[J]. J Thorac Oncol, 2011, 6(11): 1810-1817.
[15] PARK S M, LIM M K, SHIN S A, et al. Impact of prediagnosis smoking, alcohol, obesity, and insulin resistance on survival in male cancer patients: national Health Insurance Corporation Study[J]. J Clin Oncol, 2006, 24(31): 5017-5024.
[16] HWANGBO Y, LEE E K. Acute hyperglycemia associated with anti-cancer medication[J]. Endocrinol Metab, 2017, 32(1): 23-29.
[17] DAMARAJU V L, AMINPOUR M, KUZMA M, et al. Tyrosine kinase inhibitors reduce glucose uptake by binding to an exofacial site on hGLUT-1: influence on ¹⁸ F-FDG PET uptake[J]. Clin Transl Sci, 2021, 14(3): 847-858.
[18] GREMKE N, POLO P, DORT A, et al. mTOR-mediated cancer drug resistance suppresses autophagy and generates a druggable metabolic vulnerability[J]. Nat Commun, 2020, 11(1): 4684.
[19] LIN Y C, HU D, ZHOU Q, et al. The fasting blood glucose and long non-coding RNA SNHG8 predict poor prognosis in patients with gastric carcinoma after radical gastrectomy[J]. Aging, 2018, 10(10): 2646-2656.
[20] HU D, PENG F, LIN X D, et al. The elevated preoperative fasting blood glucose predicts a poor prognosis in patients with esophageal squamous cell carcinoma: the Fujian prospective investigation of cancer (FIESTA) study[J]. Oncotarget, 2016, 7(40): 65247-65256.
[21] WU N, ZHU Y J, KADEL D, et al. The prognostic influence of body mass index, resting energy expenditure and fasting blood glucose on postoperative patients with esophageal cancer[J]. BMC Gastroenterol, 2016, 16(1): 142.

Control of blood glucose on targeted therapy in EGFR-mutated lung adenocarcinoma

PDF (PC)

Knowledge

Abstract

Cite this article

share this article

References

Related Articles 11

Recommended Articles

Metrics

Comments

[1]	HUANG Conggai, LIU Qing, ZHENG Shutao, LIU Tao, TAN Yiyi, PENG Tianyuan, CHEN Jiao, LU Xiaomei. Expression of CXCR2 in esophageal cancer tissues and its impact on biological behavior of esophageal cancer cells [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2024, 36(1): 53-57,65.
[2]	LIU Ying, WANG Rui, GUO Xiao, DONG Lüli, ZHANG Yan, ZHAO Yinhuan, DU Yun. Relationships between DNA ploidy abnormality and EGFR mutation in pleural effusions, and their effects on prognosis of lung adenocarcinomas [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2023, 35(3): 178-182,186.
[3]	HUANG Lidan, WU Yueming, WANG Yadi, TAN Qi. Relationships between VEGF-A protein expression and EGFR mutation in patients with lung adenocarcinomas and its clinical significance [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2023, 35(2): 116-120.
[4]	DENG Huiyan, LIU Chang, JIA Ying, LI Fang, YIN Danjing, TAN Zirui, SU Bing, LIU Yueping. Comparative detection of the EGFR gene in lung adenocarcinoma tissues and blood samples [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2023, 35(1): 21-25.
[5]	YU Yunliang, WANG Lili, LI Ting, FENG Jiankai. Correlations among P2RX1,prognosis and immune cells infiltration in lung adenocarcinoma [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2022, 34(5): 353-360,365.
[6]	ZENG Zhuoying, WU Desheng, LU Jingjing, LIAO Hui, LAI Hongpiao, YUAN Jianhui, HU Zhangli. Mediation by estrogen receptor α on oxidative phosphorylation pathways in development of lung cancer [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2021, 33(4): 262-268.
[7]	DU Qiang, YAO Yiyong, ZENG Gang. Expression and clinical significance of ASPM in lung adenocarcinoma according to the TCGA database [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2020, 32(6): 457-463.
[8]	MA Yang, WU Juan, JI Xiaokun, WANG Rui, DU Yun, WANG Heng, GUO Xiao, ZHANG Yan. Silencing EGFR expression influenced autophagy activity in A549 cells [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2019, 31(5): 347-351,358.
[9]	GUO Xiao, WANG Rui, WU Juan, JI Xiaokun, WANG Heng, ZHANG Yan, MA Yang, DU Yun. Significance of EGFR gene mutation in fresh cytological specimens of lung adenocarcinoma [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2018, 30(1): 67-70.
[10]	LI Yuxuan, LI Kai, ZHANG Tongtong, GUO Yuanbiao, YIN Jun, BAO Yong. Heat shock protein HDJ1 on invasion and migration ability of lung adenocarcinoma cells [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2017, 29(5): 358-363.
[11]	LI Yu, YANG Su-xia, ZHOU Shu-zhen, et al. Experimental Study of Anti-tumor Effect of Baofeixiaoliu Capsule on Lung Adenocarcinoma [J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2004, 16(1): 33-35.