The pedictive value of serum soluble CD146 for EGFR-TKI acquired resistance of lung adenocarcinoma_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

LIU Chang ,  MA Lijun

Department of Critical and Respiratory Medicine, People’s Hospital of Zhengzhou University, zhengzhou, Henan 450000, P. R. China;

Corresponding author：

MA Lijun, Email: malijun1958@126.com

Keywords：

Soluble CD146; Lung adenocarcinoma; Epidermal growth factor receptor-tyrosine kinase inhibitor; Acquired drug resistance

DOI：

10.7507/1671-6205.201709021

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ObjectiveTo investigate the value of serum soluble CD146 (sCD146) in determining acquired epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance in lung adenocarcinoma.MethodsA total of 144 lung adenocarcinoma EGFR sensitive patients in People’s Hospital of Zhengzhou University diagnosed from January 2016 to December 2016 were recruited in the study. According to the different time of taking drugs, the patients were divided into a non-medication group (31 cases), a 1 to 3 month treatment group (25 cases), a 4 to 6 month treatment group (19 cases), a 7 to 12 month treatment group (25 cases), a drug-resistant group (24 cases), and a nonresistant group up to 1 year of treatment (20 cases). The serum levels of sCD146, carcinoembryonic antigen (CEA) and neuron-specific enolase (NSE) were measured by ELISA and chemiluminescence and compared between different period of medication. The relationship of serum sCD146 with tumor markers (CEA, NSE) and tumor related clinical parameters (age, gender, tumor stage, metastasis, tumor diameter, number of the lesions) were analyzed.ResultsThe serum sCD146 level was minimum in the non-medication group that did not receive pioglitazone treatment, highest in the 1 to 3 month treatment group (early treatment period), and declined with duration of medication until resistance occurred without significant difference (P>0.05). The level of sCD146 of the drug-resistant group was significantly lower than that of all nonresistant groups, with significant difference (allP<0.05), but still higher than that of the non-medication group (P<0.05). The serum sCD146 levels in the nonresistant patients with medication over 1 year and within 1 year were similar (P>0.05), and significantly higher than the non-medication group and drug-resistance group (allP<0.05). The serum CEA levels did not differ significantly between 6 groups (P>0.05). The serum NSE level of the 4 to 6 month treatment group was lower than that of the 7 to 12 month treatment group (P<0.05), but both in the normal reference range. The NSE levels did not differ in any other groups (P>0.05). Serum sCD146 was associated with metastasis (P<0.05), but not associated with serum CEA or NSE, nor with sex, age, tumor staging, tumor diameter or lesion number (allP>0.05).ConclusionsCD146 may be involved in the mechanism of TKI killing tumor cells and the mechanism of TKI resistance, and may be a serological marker for monitoring the efficacy of TKI and judging the resistance of TKI.

Citation： LIU Chang, MA Lijun. The pedictive value of serum soluble CD146 for EGFR-TKI acquired resistance of lung adenocarcinoma. Chinese Journal of Respiratory and Critical Care Medicine, 2018, 17(2): 155-160. doi: 10.7507/1671-6205.201709021 Copy

1.	钱桂生. 肺癌流行病学与启示. 中国临床医生杂志, 2009, 37(9): 3-4.
2.	钱桂生, 余时沧. 肺癌流行病学最新资料与启示. 中华结核和呼吸杂志, 2012, 35(2): 86-89.
3.	Le CT, Scagliotti G, Natale R, et al. Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes. Lung Cancer (Amsterdam, Netherlands), 2005, 47(1): 69.
4.	Herbst RS, Heymach JV, Lippman SM. Molecular origins of cancer: lung cancer. N Engl J Med, 2008, 359(13): 1367-1380.
5.	Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med, 2009, 361(10): 947-957.
6.	Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med, 2005, 352(8): 786-792.
7.	Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med, 2005, 2(3): e73.
8.	Bean J, Brennan C, Shih JY, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A, 2007, 104(52): 20932-20937.
9.	Turke AB, Zejnullahu K, Wu YL, et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer cell, 2010, 17(1): 77-88.
10.	Metro G, Chiari R, Duranti S, et al. Impact of specific mutant KRAS on clinical outcome of EGFR-TKI-treated advanced non-small cell lung cancer patients with an EGFR wild type genotype. Lung Cancer, 2012, 78(1): 81-86.
11.	Uramoto H, Iwata T, Onitsuka T, et al. Epithelial-mesenchymal transition in EGFR-TKI acquired resistant lung adenocarcinoma. Anticancer Res, 2010, 30(7): 2513-2517.
12.	Thiery JP, Acloque H, Huang RY, et al. Epithelial-mesenchymal transitions in development and disease. Cell, 2014, 139(5): 871.
13.	Zeng Q, Li W, Lu D, et al. CD146, an epithelial-mesenchymal transition inducer, is associated with triple-negative breast cancer. Proc Natl Acad Sci U S A, 2012, 109(4): 1127-1132.
14.	Ye Z, Zhang C, Tu T, et al. Wnt5a uses CD146 as a receptor to regulate cell motility and convergent extension. Nature Commun, 2013, 4(1): 2803.
15.	Liang YK, Zeng D, Xiao YS, et al. MCAM/CD146 promotes tamoxifen resistance in breast cancer cells through induction of epithelial-mesenchymal transition, decreased ERα expression and AKT activation. Cancer Letters, 2017, 386: 65-76.
16.	Liu WF, Ji S R, Sun J J, et al. CD146 expression correlates with epithelial-mesenchymal transition markers and a poor prognosis in gastric cancer. Int J Mol Sci, 2012, 13(5): 6399-6406.
17.	张晓菊, 安云霞, 汪铮, 等. 上皮间质转化及 CD146 和 N-cadherin 在判定肺腺癌 EGFR-TKI 获得性耐药中的作用. 中华实用诊断与治疗杂志, 2014, 28(9): 849-851.
18.	Johnson JP, Rothbächer U, Sers C. The progression associated antigen MUC18: a unique member of the immunoglobulin supergene family. Melanoma Res, 1993, 3(5): 337-340.
19.	Shih IM. The role of CD146 (Mel-CAM) in biology and pathology. J Pathol, 1999, 189(1): 4-11.
20.	Yan X, Lin Y, Yang D, et al. A novel anti-CD146 monoclonal antibody, AA98, inhibits angiogenesis and tumor growth. Blood, 2003, 102(1): 184-191.
21.	Wu GJ, Varma VA, Wu MWH, et al. Expression of a human cell adhesion molecule, MUC18, in prostate cancer cell lines and tissues. Prostate, 2001, 48(4): 305-315.
22.	樊静, 任红, 张芳, 等. 肺癌组织 CD105 和 CD146 表达及其临床意义的研究. 中华肿瘤防治杂志, 2011, 18(21): 1685-1687.
23.	Dogan I, Karyagar S, Karyagar SS, et al. Relationship between pretreatment levels of serum Cyfra 21.1, CEA and PET metabolic parameters in NSCLC. Ann Nucl Med, 2014, 28(9): 829-835.
24.	Rudin CM, Durinck S, Stawiski EW, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet, 2012, 44(10): 1111.
25.	Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res, 2013, 19(8): 2240-2247.
26.	Watanabe S, Sone T, Matsui T, et al. Transformation to small-cell lung cancer following treatment with EGFR tyrosine kinase inhibitors in a patient with lung adenocarcinoma. Lung Cancer, 2013, 82(2): 370-372.

1. 钱桂生. 肺癌流行病学与启示. 中国临床医生杂志, 2009, 37(9): 3-4.
2. 钱桂生, 余时沧. 肺癌流行病学最新资料与启示. 中华结核和呼吸杂志, 2012, 35(2): 86-89.
3. Le CT, Scagliotti G, Natale R, et al. Efficacy of gemcitabine plus platinum chemotherapy compared with other platinum containing regimens in advanced non-small-cell lung cancer: a meta-analysis of survival outcomes. Lung Cancer (Amsterdam, Netherlands), 2005, 47(1): 69.
4. Herbst RS, Heymach JV, Lippman SM. Molecular origins of cancer: lung cancer. N Engl J Med, 2008, 359(13): 1367-1380.
5. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med, 2009, 361(10): 947-957.
6. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med, 2005, 352(8): 786-792.
7. Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med, 2005, 2(3): e73.
8. Bean J, Brennan C, Shih JY, et al. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A, 2007, 104(52): 20932-20937.
9. Turke AB, Zejnullahu K, Wu YL, et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer cell, 2010, 17(1): 77-88.
10. Metro G, Chiari R, Duranti S, et al. Impact of specific mutant KRAS on clinical outcome of EGFR-TKI-treated advanced non-small cell lung cancer patients with an EGFR wild type genotype. Lung Cancer, 2012, 78(1): 81-86.
11. Uramoto H, Iwata T, Onitsuka T, et al. Epithelial-mesenchymal transition in EGFR-TKI acquired resistant lung adenocarcinoma. Anticancer Res, 2010, 30(7): 2513-2517.
12. Thiery JP, Acloque H, Huang RY, et al. Epithelial-mesenchymal transitions in development and disease. Cell, 2014, 139(5): 871.
13. Zeng Q, Li W, Lu D, et al. CD146, an epithelial-mesenchymal transition inducer, is associated with triple-negative breast cancer. Proc Natl Acad Sci U S A, 2012, 109(4): 1127-1132.
14. Ye Z, Zhang C, Tu T, et al. Wnt5a uses CD146 as a receptor to regulate cell motility and convergent extension. Nature Commun, 2013, 4(1): 2803.
15. Liang YK, Zeng D, Xiao YS, et al. MCAM/CD146 promotes tamoxifen resistance in breast cancer cells through induction of epithelial-mesenchymal transition, decreased ERα expression and AKT activation. Cancer Letters, 2017, 386: 65-76.
16. Liu WF, Ji S R, Sun J J, et al. CD146 expression correlates with epithelial-mesenchymal transition markers and a poor prognosis in gastric cancer. Int J Mol Sci, 2012, 13(5): 6399-6406.
17. 张晓菊, 安云霞, 汪铮, 等. 上皮间质转化及 CD146 和 N-cadherin 在判定肺腺癌 EGFR-TKI 获得性耐药中的作用. 中华实用诊断与治疗杂志, 2014, 28(9): 849-851.
18. Johnson JP, Rothbächer U, Sers C. The progression associated antigen MUC18: a unique member of the immunoglobulin supergene family. Melanoma Res, 1993, 3(5): 337-340.
19. Shih IM. The role of CD146 (Mel-CAM) in biology and pathology. J Pathol, 1999, 189(1): 4-11.
20. Yan X, Lin Y, Yang D, et al. A novel anti-CD146 monoclonal antibody, AA98, inhibits angiogenesis and tumor growth. Blood, 2003, 102(1): 184-191.
21. Wu GJ, Varma VA, Wu MWH, et al. Expression of a human cell adhesion molecule, MUC18, in prostate cancer cell lines and tissues. Prostate, 2001, 48(4): 305-315.
22. 樊静, 任红, 张芳, 等. 肺癌组织 CD105 和 CD146 表达及其临床意义的研究. 中华肿瘤防治杂志, 2011, 18(21): 1685-1687.
23. Dogan I, Karyagar S, Karyagar SS, et al. Relationship between pretreatment levels of serum Cyfra 21.1, CEA and PET metabolic parameters in NSCLC. Ann Nucl Med, 2014, 28(9): 829-835.
24. Rudin CM, Durinck S, Stawiski EW, et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet, 2012, 44(10): 1111.
25. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res, 2013, 19(8): 2240-2247.
26. Watanabe S, Sone T, Matsui T, et al. Transformation to small-cell lung cancer following treatment with EGFR tyrosine kinase inhibitors in a patient with lung adenocarcinoma. Lung Cancer, 2013, 82(2): 370-372.

Chinese Journal of Respiratory and Critical Care Medicine

The pedictive value of serum soluble CD146 for EGFR-TKI acquired resistance of lung adenocarcinoma

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