药学学报, 2019, 54(8): 1364-1371
引用本文:
王晨, 陈淑珍. 非小细胞肺癌治疗药物EGFR-TKIs获得性耐药机制的研究进展[J]. 药学学报, 2019, 54(8): 1364-1371.
WANG Chen, CHEN Shu-zhen. Advances in the mechanisms of acquired resistance to EGFR-tyrosine kinase inhibitors in non-small cell lung cancer[J]. Acta Pharmaceutica Sinica, 2019, 54(8): 1364-1371.

非小细胞肺癌治疗药物EGFR-TKIs获得性耐药机制的研究进展
王晨, 陈淑珍
中国医学科学院、北京协和医学院医药生物技术研究所, 北京 100050
摘要:
肺癌在所有肿瘤中死亡率占第一位,其中非小细胞肺癌(NSCLC)占肺癌发病率的80%左右。近年来,分子靶向药物发展迅速,其中表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)以表皮生长因子受体(EGFR)作为靶点,在治疗NSCLC患者中取得很好的疗效,目前有三代EGFR-TKIs在临床上使用,效果优于传统化疗,但是也都出现获得性耐药的问题。本文将获得性耐药机制的研究进展分为依赖EGFR通路和非依赖EGFR通路两部分作一综述。依赖EGFR通路主要介绍EGFR的基因突变,非依赖EGFR通路包括HER2的扩增、BIM缺失、HGF/c-MET通路的激活、IGF1R的活化、RAS突变、PTEN缺失、上皮-间充质转化、PUMA表达下调、IL-6和VEGF高表达,这些耐药机制相互联系,相互影响,使肿瘤细胞对EGFR-TKIs产生耐药。
关键词:    非小细胞肺癌      表皮生长因子受体酪氨酸激酶抑制剂      获得性耐药      表皮生长因子受体依赖性      表皮生长因子受体非依赖性     
Advances in the mechanisms of acquired resistance to EGFR-tyrosine kinase inhibitors in non-small cell lung cancer
WANG Chen, CHEN Shu-zhen
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
Lung cancer ranks the first in the mortality rate among all cancers, and non-small cell lung carcinoma (NSCLC) accounts for about 80% of the incidence of lung cancer. In recent years, the drugs targeting specific molecules have been developed rapidly. The epidermal growth factor receptor-tyrosine kinase inhibitors (EGFRTKIs) have achieved good results in the treatment of patients with NSCLC. Currently, there are three generations of EGFR-TKIs, and the treatment outcome of these drugs surpasses traditional chemotherapies. However, the problems of acquired resistance remains in the course of treatment. In this review, research progress of the mechanisms of acquired resistance is divided into two parts:EGFR-dependent pathway and EGFR-independent pathway. The EGFR-dependent pathway mainly includes EGFR gene mutations, whereas the EGFR-independent pathways include HER2 amplification, BIM deletion, activation of HGF/c-Met pathway, activation of IGF1R, RAS mutation, PTEN deletion, epithelial-mesenchymal transition, PUMA loss, and high levels of expression of VEGF or IL-6. These interconnected mechanisms are linked with acquired resistance to EGFR-TKIs in NSCLC.
Key words:    non-small cell lung cancer    epidermal growth factor receptor-tyrosine kinase inhibitor    acquired resistance    EGFR-dependence    EGFR-independence   
收稿日期: 2019-01-24
DOI: 10.16438/j.0513-4870.2019-0089
基金项目: 国家自然科学基金资助项目(81621064);中国医学科学院医学与健康科技创新工程(2016-I2M-2-002);重大新药创制科技重大专项(2018ZX09711001-007-002).
通讯作者: 陈淑珍,Tel:86-10-63166305,Fax:86-10-63138137,E-mail:bjcsz@imb.pumc.edu.cn
Email: bjcsz@imb.pumc.edu.cn
相关功能
PDF(398KB) Free
打印本文
0
作者相关文章
王晨  在本刊中的所有文章
陈淑珍  在本刊中的所有文章

参考文献:
[1] Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs[J]. JAMA, 2014, 311:1998-2006.
[2] Ma Y, Xin S, Huang M, et al. Determinants of gefitinib toxicity in advanced non-small cell lung cancer (NSCLC):a pharmacogenomic study of metabolic enzymes and transporters[J]. Pharmacogenomics J, 2017, 17:325-330.
[3] Jia Y, Yun CH, Park E, et al. Overcoming EGFR (T790M) and EGFR (C797S) resistance with mutant-selective allosteric inhibitors[J]. Nature, 2016, 534:129-132.
[4] Shi P, Oh YT, Deng L, et al. overcoming acquired resistance to AZD9291, a third-generation EGFR inhibitor, through modulation of MEK/ERK dependent BIM and Mcl-1 degradation[J]. Clin Cancer Res, 2017, 23:6567-6579.
[5] Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer[J]. N Engl J Med, 2009, 361:958-967.
[6] Yun CH,Mengwasser KE, Toms AV, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP[J]. Proc Natl Acad Sci U S A, 2008, 105:2070-2075.
[7] Jackman D, Pao W, Riely GJ, et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer[J]. J Clin Oncol, 2010, 28:357-360.
[8] Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC):a multicentre, open-label, randomised phase 3 trial[J]. Lancet Oncol, 2012, 13:239-246.
[9] Roskoski R Jr. Small molecule inhibitors targeting the EGFR/ErbB family of protein-tyrosine kinases in human cancers[J]. Pharmacol Res, 2019, 139:395-411.
[10] Yang JC, Wu YL, Schuler M, et al. Afatinib versus cisplatinbased chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6):analysis of overall survival data from two randomised, phase 3 trials[J]. Lancet Oncol, 2015, 16:141-151.
[11] 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[J]. Clin Cancer Res, 2013, 19:2240-2247.
[12] Ercan D, Choi HG, Yun CH, et al. EGFR mutations and resistance to irreversible pyrimidine based EGFR inhibitors[J]. Clin Cancer Res, 2015, 21:3913-3923.
[13] Thress KS, Paweletz CP, Felip E, et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M[J]. Nat Med, 2015, 21:560-562.
[14] Takezawa K, Pirazzoli V, Arcila ME, et al. HER2 amplification:a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFR T790M mutation[J]. Cancer Discov, 2012, 2:922-933.
[15] Planchard D, Loriot Y, André F, et al. EGFR-independent mechanisms of acquired resistance to AZD9291 in EGFR T790M-positive NSCLC patients[J]. Ann Oncol, 2015, 26:2073-2078.
[16] Ng KP, Hillmer AM, Chuah CT, et al. A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer[J]. Nat Med, 2012, 18:521-528.
[17] Ma JY, Yan HJ, Gu W, et al. Association between BIM deletion polymorphism and clinical outcome of EGFR-mutated NSCLC patient with EGFR-TKI therapy:a meta-analysis[J]. J Cancer Res Ther, 2015, 11:397-402.
[18] Chen H, Wang Y, Lin C, et al. Vorinostat and metformin sensitize EGFR-TKI resistant NSCLC cells via BIM-dependent apoptosis induction[J]. Oncotarget, 2017, 8:93825-93838.
[19] Suda K, Murakami I, Katayama T, et al. Reciprocal and complementary role of MET amplification and EGFR T790M mutation in acquired resistance to kinase inhibitors in lung cancer[J]. Clin Cancer Res, 2010, 16:5489-5498.
[20] Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling[J]. Science, 2007, 316:1039-1043.
[21] Shi P, Oh YT, Zhang G, et al. MET gene amplification and protein hyperactivation is a mechanism of resistance to both first and third generation EGFR inhibitors in lung cancer treatment[J]. Cancer Lett, 2016, 380:494-504.
[22] Yang H, Wang R, Peng S, et al. Hepatocyte growth factor reduces sensitivity to the epidermal growth factor receptor-tyrosine kinase inhibitor, gefitinib, in lung adenocarcinoma cells harboring wildtype EGFR[J]. Oncotarget, 2016, 7:16273-16281.
[23] Jang JY, Kim YG, Nam SJ, et al. Targeting adenine nucleotide translocase-2(ANT2) to overcome resistance to epidermal growth factor receptor tyrosine kinase inhibitor in non-small cell lung cancer[J]. Mol Cancer Ther, 2016, 15:1387-1396.
[24] Deng QF, Su BO, Zhao YM, et al. Integrin β1-mediated acquired gefitinib resistance in non-small cell lung cancer cells occurs via the phosphoinositide 3-kinase-dependent pathway[J]. Oncol Lett, 2016, 11:535-542.
[25] Yi Y, Zeng S, Wang Z, et al. Cancer-associated fibroblasts promote epithelial-mesenchymal transition and EGFR-TKI resistance of non-small cell lung cancers via HGF/IGF-1/ANXA2 signaling[J]. Biochim Biophys Acta Mol Basis Dis, 2018, 1864:793-803.
[26] Chen Z, Han J, Zhao F, et al. miR-223 reverses the resistance of EGFR-TKIs through IGF1R/PI3K/AKT signaling pathway[J]. Int J Oncol, 2016, 48:1855-1867.
[27] Suda K, Mizuuchi H, Sato K, et al. The insulin-like growth factor 1 receptor causes acquired resistance to erlotinib in lung cancer cells with the wild-type epidermal growth factor receptor[J]. Int J Cancer, 2014, 135:1002-1006.
[28] Guerard M, Robin T, Perron P, et al. Nuclear translocation of IGF1R by intracellular amphiregulin contributes to the resistance of lung tumour cells to EGFR-TKI[J]. Cancer Lett, 2018, 420:146-155.
[29] Dearden S, Stevens J, Wu YL, et al. Mutation incidence and coincidence in non-small-cell lung cancer:meta-analyses by ethnicity and histology (mutMap)[J]. Ann Oncol, 2013, 24:2371-2376.
[30] Ohba T, Toyokawa G, Kometani T, et al. The mutations of the EGFR and k-RAS genes in resected stage I lung adenocarcinoma and their clinical significance[J]. Surg Today, 2014, 44:478-486.
[31] Zhou B, Tang C, Li J. k-RAS mutation and resistance to epidermal growth factor receptor-tyrosine kinase inhibitor treatment in patients with non-small cell lung cancer[J]. J Can Res Ther, 2017, 13:699-701.
[32] Yamaoka T, Ohmori T, Ohba M, et al. Distinct afatinib resistance mechanisms identified in lung adenocarcinoma harboring an EGFR mutation[J]. Mol Cancer Res, 2017, 15:915-928.
[33] Han L, Guo XJ, Chen Z, et al. The mechanisms of paeonol reversing multidrug resistance in ovarian cancer SKOV3/DDP cells[J]. Acta Pharm Sin (药学学报), 2018, 53:1511-1517.
[34] Sos ML, Koker M, Weir BA, et al. PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of AKT and EGFR[J]. Cancer Res, 2009, 69:3256-3261.
[35] To KKW, Wu WKK, Loong HHF, et al. PPARgamma agonists sensitize PTEN-deficient resistant lung cancer cells to EGFR tyrosine kinase inhibitors by inducing autophagy[J]. Eur J Pharmacol, 2018, 823:19-26.
[36] Ma Y, Liu H, Zhang H, et al. The TGF-β signaling pathway induced EMT in breast cancer[J]. Acta Pharm Sin (药学学报), 2015, 50:385-392.
[37] Shibue T, Weinberg RA. EMT, CSCs, and drug resistance:the mechanistic link and clinical implications[J]. Nat Rev Clin Oncol, 2017, 14:611-629.
[38] Li L, Gu X, Yue J, et al. Acquisition of EGFR TKI resistance and EMT phenotype is linked with activation of IGF1R/NFkappaB pathway in EGFR-mutant NSCLC[J]. Oncotarget, 2017, 8:92240-92253.
[39] Yochum ZA, Cades J, Wang H, et al. Targeting the EMT transcription factor TWIST1 overcomes resistance to EGFR inhibitors in EGFR-mutant non-small-cell lung cancer[J]. Oncogene, 2019, 38:656-670.
[40] Sun Q, Ming L, Thomas SM, et al. PUMA mediates EGFR tyrosine kinase inhibitor-induced apoptosis in head and neck cancer cells[J]. Oncogene, 2009, 28:2348-2357.
[41] Han X, Liu M, Wang S, et al. An integrative analysis of the putative gefitinib-resistance related genes in a lung cancer cell line model system[J]. Curr Cancer Drug Targets, 2015, 15:423-434.
[42] Li L, Han R, Xiao H, et al. Metformin sensitizes EGFR-TKIresistant human lung cancer cells in vitro and in vivo through inhibition of IL-6 signaling and EMT reversal[J]. Clin Cancer Res, 2014, 20:2714-2726.
[43] Tamura T, Kato Y, Ohashi K, et al. Potential influence of interleukin-6 on the therapeutic effect of gefitinib in patients with advanced non-small cell lung cancer harbouring EGFR mutations[J]. Biochem Biophys Res Commun, 2018, 495:360-367.
[44] Li F, Zhu T, Cao B, et al. Apatinib enhances antitumour activity of EGFR-TKIs in non-small cell lung cancer with EGFR-TKI resistance[J]. Eur J Cancer, 2017, 84:184-192.
[45] Li Y, Wang Y, Niu K, et al. Clinical benefit from EGFR-TKI plus ginsenoside Rg3 in patients with advanced non-small cell lung cancer harboring EGFR active mutation[J]. Oncotarget, 2016, 7:70535-70545.
[46] Tung JN, Lin PL, Wang YC, et al. PD-L1 confers resistance to EGFR mutation-independent tyrosine kinase inhibitors in nonsmall cell lung cancer via upregulation of YAP1 expression[J]. Oncotarget, 2018, 9:4637-4646.
[47] Kunimasa K, Nakamura H, Sakai K, et al. Heterogeneity of EGFR-mutant clones and PD-L1 highly expressing clones affects treatment efficacy of EGFR-TKI and PD-1 inhibitor[J]. Ann Oncol, 2018, 29:2145-2147.
[48] Su S, Dong ZY, Xie Z, et al. Strong programmed death ligand 1 expression predicts poor response and de novo resistance to EGFR tyrosine kinase inhibitors among NSCLC patients with EGFR mutation[J]. J Thorac Oncol, 2018, 13:1668-1675.
[49] Kobayashi K, Seike M, Zou F, et al. Prognostic significance of NSCLC and response to EGFR-TKIs of EGFR-mutated NSCLC based on PD-L1 expression[J]. Anticancer Res, 2018, 38:753-762.
[50] Suda K, Rozeboom L, Furugaki K, et al. Increased EGFR phosphorylation correlates with higher programmed death ligand-1 expression:analysis of TKI-resistant lung cancer cell lines[J]. Biomed Res Int, 2017, 2017:7694202.