非小细胞肺癌第三代表皮生长因子受体-酪氨酸激酶抑制剂的耐药机制及治疗策略

doi:10.3969/j.issn.1674-8115.2022.04.017

上海交通大学学报（医学版） ›› 2022, Vol. 42 ›› Issue (4): 535-544.doi: 10.3969/j.issn.1674-8115.2022.04.017

非小细胞肺癌第三代表皮生长因子受体-酪氨酸激酶抑制剂的耐药机制及治疗策略

陆文清(), 孟周文理(), 虞永峰, 陆舜()

上海交通大学医学院附属胸科医院肿瘤科，上海 200030

收稿日期:2021-12-31 接受日期:2022-03-19 出版日期:2022-04-28 发布日期:2022-04-28
通讯作者: 陆舜 E-mail:lwq817@sjtu.edu.cn;yzmzwl@yeah.net;shunlu@sjtu.edu.cn
作者简介:陆文清（1998—），女，博士生；电子信箱：lwq817@sjtu.edu.cn
孟周文理（1995—），男，博士生；电子信箱：yzmzwl@yeah.net。第一联系人：为共同第一作者。
基金资助:
国家自然科学基金(82030045)

Resistance mechanisms and overcoming strategies of the third-generation EGFR-TKI in non-small cell lung cancer

LU Wenqing(), MENG Zhouwenli(), YU Yongfeng, LU Shun()

Department of Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China

Received:2021-12-31 Accepted:2022-03-19 Online:2022-04-28 Published:2022-04-28
Contact: LU Shun E-mail:lwq817@sjtu.edu.cn;yzmzwl@yeah.net;shunlu@sjtu.edu.cn
Supported by:
National Natural Science Foundation of China(82030045)

摘要/Abstract

摘要：

表皮生长因子受体（epidermal growth factor receptor，EGFR）基因是非小细胞肺癌最常见的驱动基因。针对EGFR突变的酪氨酸激酶抑制剂（tyrosine kinase inhibitors，TKIs）是EGFR突变患者的一线治疗首选方案。虽然第一、二、三代TKIs已经广泛应用于临床，但无法避免的继发耐药和部分初治患者的原发耐药，仍旧给长线用药带来了巨大挑战。一代以及二代EGFR-TKIs的耐药机制研究较为清楚，包括T790M突变、MET扩增、ERBB2扩增、IGF1R上调、AXL活化等。第三代TKIs可克服前2代最常见的T790M突变，但是随其在临床应用的日益广泛，耐药问题正引起广泛的重视，相关机制和治疗策略目前仍在研究中。机制分为EGFR依赖性和非依赖性2种，包括靶基因突变、旁路信号通路激活、表型转化、表观遗传调控以及免疫抑制微环境等。第四代TKIs、联合治疗以及免疫治疗等都是潜在的耐药后治疗方式。

关键词: 非小细胞肺癌, 表皮生长因子受体, 蛋白激酶抑制剂, 耐药性

Abstract:

Epidermal growth factor receptor (EGFR) gene is the most common driver gene of non-small cell lung cancer. Tyrosine kinase inhibitors (TKIs) targeting EGFR mutations are the first-line treatment choice for patients with EGFR mutations. Although three generations of drugs have been widely used in clinical practice, unavoidable secondary resistance and primary resistance to some treatment-naive patients still pose great challenges to the long-term use of EGFR-TKIs. Resistance mechanism of the first- and second-generation EGFR-TKIs are well studied, including T790M mutation, MET amplification, ERBB2 amplification, IGF1R up-regulation, AXL activation, etc. The third-generation TKIs can overcome the most common T790M mutation that the first two generations bring in, but with the increasingly widespread clinical use, their drug resistance problem is also attracting widespread attention, and the related mechanisms and overcoming strategies are still under study. Mechanisms can be divided into EGFR-dependent and EGFR-independent ones, involving target-gene mutation, bypass signaling activation, phenotypic plasticity, epigenetic regulation, inhibitory immune microenvironment and so on. The fourth-generation TKIs, combination therapy and immunotherapy are all potential modalities after drug resistance.

Key words: non-small cell lung cancer, epidermal growth factor receptor (EGFR), protein kinase inhibitor, drug resistance

中图分类号:

R734.2

陆文清, 孟周文理, 虞永峰, 陆舜. 非小细胞肺癌第三代表皮生长因子受体-酪氨酸激酶抑制剂的耐药机制及治疗策略[J]. 上海交通大学学报（医学版）, 2022, 42(4): 535-544.

LU Wenqing, MENG Zhouwenli, YU Yongfeng, LU Shun. Resistance mechanisms and overcoming strategies of the third-generation EGFR-TKI in non-small cell lung cancer[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(4): 535-544.

图/表 1

参考文献 71

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	WU L L, KE L P, ZHANG Z S, et al. Development of EGFR TKIs and options to manage resistance of third-generation EGFR TKI osimertinib: conventional ways and immune checkpoint inhibitors[J]. Front Oncol, 2020, 10: 602762.
3	YUN C H, MENGWASSER K E, TOMS A V, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP[J]. Proc Natl Acad Sci USA, 2008, 105(6): 2070-2075.
4	BALAK M N, GONG Y X, RIELY G J, et al. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors[J]. Clin Cancer Res, 2006, 12(21): 6494-6501.
5	COSTA D B, SCHUMER S T, TENEN D G, et al. Differential responses to erlotinib in epidermal growth factor receptor (EGFR)-mutated lung cancers with acquired resistance to gefitinib carrying the L747S or T790M secondary mutations[J]. J Clin Oncol, 2008, 26(7): 1182-1184.
6	ARCILA M E, NAFA K, CHAFT J E, et al. EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics[J]. Mol Cancer Ther, 2013, 12(2): 220-229.
7	YU H A, ARCILA M E, 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(8): 2240-2247.
8	ABOUNADER R, LATERRA J. Scatter factor/hepatocyte growth factor in brain tumor growth and angiogenesis[J]. Neuro-Oncology, 2005, 7(4): 436-451.
9	GANDARA D R, LI T H, LARA P N, et al. Acquired resistance to targeted therapies against oncogene-driven non-small-cell lung cancer: approach to subtyping progressive disease and clinical implications[J]. Clin Lung Cancer, 2014, 15(1): 1-6.
10	SORIA J C, WU Y L, NAKAGAWA K, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial[J]. Lancet Oncol, 2015, 16(8): 990-998.
11	PARK K, YU C J, KIM S W, et al. First-line erlotinib therapy until and beyond response evaluation criteria in solid tumors progression in Asian patients with epidermal growth factor receptor mutation-positive non-small-cell lung cancer: the ASPIRATION study[J]. JAMA Oncol, 2016, 2(3): 305-312.
12	YU H A, SIMA C S, HUANG J, et al. Local therapy with continued EGFR tyrosine kinase inhibitor therapy as a treatment strategy in EGFR-mutant advanced lung cancers that have developed acquired resistance to EGFR tyrosine kinase inhibitors[J]. J Thorac Oncol, 2013, 8(3): 346-351.
13	TAN C S, CHO B C, SOO R A. Treatment options for EGFR mutant NSCLC with CNS involvement-Can patients BLOOM with the use of next generation EGFR TKIs? [J]. Lung Cancer, 2017, 108: 29-37.
14	CROSS D A E, ASHTON S E, GHIORGHIU S, et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer[J]. Cancer Discov, 2014, 4(9): 1046-1061.
15	MOK T S, WU Y L, AHN M J, et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer[J]. N Engl J Med, 2017, 376(7): 629-640.
16	RAMALINGAM S S, VANSTEENKISTE J, PLANCHARD D, et al. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC[J]. N Engl J Med, 2020, 382(1): 41-50.
17	WU Y L, TSUBOI M, HE J, et al. Osimertinib in resected EGFR-mutated non-small-cell lung cancer[J]. N Engl J Med, 2020, 383(18): 1711-1723.
18	AHN M J, HAN J Y, LEE K H, et al. Lazertinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: results from the dose escalation and dose expansion parts of a first-in-human, open-label, multicentre, phase 1-2 study[J]. Lancet Oncol, 2019, 20(12): 1681-1690.
19	SHI Y K, HU X S, ZHANG S C, et al. Efficacy, safety, and genetic analysis of furmonertinib (AST2818) in patients with EGFR T790M mutated non-small-cell lung cancer: a phase 2b, multicentre, single-arm, open-label study[J]. Lancet Respir Med, 2021, 9(8): 829-839.
20	SCHOENFELD A J, CHAN J M, RIZVI H, et al. Tissue-based molecular and histological landscape of acquired resistance to osimertinib given initially or at relapse in patients with EGFR-mutant lung cancers[J]. J Clin Oncol, 2019, 37(15_suppl): 9028.
21	WENG C H, CHEN L Y, LIN Y C, et al. Epithelial-mesenchymal transition (EMT) beyond EGFR mutations per se is a common mechanism for acquired resistance to EGFR TKI[J]. Oncogene, 2019, 38(4): 455-468.
22	NIEDERST M J, HU H C, MULVEY H E, et al. The allelic context of the C797S mutation acquired upon treatment with third-generation EGFR inhibitors impacts sensitivity to subsequent treatment strategies[J]. Clin Cancer Res, 2015, 21(17): 3924-3933.
23	TANG Z H, LU J J. Osimertinib resistance in non-small cell lung cancer: mechanisms and therapeutic strategies[J]. Cancer Lett, 2018, 420: 242-246.
24	LE X N, PURI S, NEGRAO M V, et al. Landscape of EGFR-dependent and-independent resistance mechanisms to osimertinib and continuation therapy beyond progression in EGFR-mutant NSCLC[J]. Clin Cancer Res, 2018, 24(24): 6195-6203.
25	PELED N, ROISMAN L C, MIRON B, et al. Subclonal therapy by two EGFR TKIs guided by sequential plasma cell-free DNA in EGFR-mutated lung cancer[J]. J Thorac Oncol, 2017, 12(7): e81-e84.
26	STARRETT J H, GUERNET A A, CUOMO M E, et al. Drug sensitivity and allele specificity of first-line osimertinib resistance EGFR mutations[J]. Cancer Res, 2020, 80(10): 2017-2030.
27	LIN Y T, TSAI T H, WU S G, et al. Complex EGFR mutations with secondary T790M mutation confer shorter osimertinib progression-free survival and overall survival in advanced non-small cell lung cancer[J]. Lung Cancer, 2020, 145: 1-9.
28	OXNARD G R, HU Y B, MILEHAM K F, et al. Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib[J]. JAMA Oncol, 2018, 4(11): 1527-1534.
29	LEE J Y, KIM H S, LEE B, et al. Genomic landscape of acquired resistance to third-generation EGFR tyrosine kinase inhibitors in EGFR T790M-mutant non-small cell lung cancer[J]. Cancer, 2020, 126(11): 2704-2712.
30	PIOTROWSKA Z, NAGY R, FAIRCLOUGH S, et al. OA 09.01 characterizing the genomic landscape of EGFR C797S in lung cancer using ctDNA next-generation sequencing[J]. J Thorac Oncol, 2017, 12(11): S1767.
31	WANG Z, YANG J J, HUANG J, et al. Lung adenocarcinoma harboring EGFR T790M and in trans C797S responds to combination therapy of first- and third-generation EGFR TKIs and shifts allelic configuration at resistance[J]. J Thorac Oncol, 2017, 12(11): 1723-1727.
32	RAMALINGAM S S, CHENG Y, ZHOU C, et al. Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase Ⅲ FLAURA study[J]. Ann Oncol, 2018, 29: viii740.
33	ENGELMAN J A, ZEJNULLAHU K, MITSUDOMI T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB₃ signaling[J]. Science, 2007, 316(5827): 1039-1043.
34	HSU C C, LIAO B C, LIAO W Y, et al. Exon 16-skipping HER2 as a novel mechanism of osimertinib resistance in EGFR L858R/T790M-positive non-small cell lung cancer[J]. J Thorac Oncol, 2020, 15(1): 50-61.
35	HANAHAN D. Hallmarks of cancer: new dimensions[J]. Cancer Discov, 2022, 12(1): 31-46.
36	QUINTANAL-VILLALONGA Á, CHAN J M, YU H A, et al. Lineage plasticity in cancer: a shared pathway of therapeutic resistance[J]. Nat Rev Clin Oncol, 2020, 17(6): 360-371.
37	MARCOUX N, GETTINGER S N, O'KANE G, et al. EGFR-mutant adenocarcinomas that transform to small-cell lung cancer and other neuroendocrine carcinomas: clinical outcomes[J]. J Clin Oncol, 2019, 37(4): 278-285.
38	QUINTANAL-VILLALONGA A, TANIGUCHI H, ZHAN Y A, et al. Multi-omic analysis of lung tumors defines pathways activated in neuroendocrine transformation[J]. Cancer Discov, 2021, 11(12):3028-3047.
39	KUO M H, LEE A C, HSIAO S H, et al. Cross-talk between SOX2 and TGFβ signaling regulates EGFR–TKI tolerance and lung cancer dissemination[J]. Cancer Res, 2020, 80(20): 4426-4438.
40	LOTSBERG M L, WNUK-LIPINSKA K, TERRY S, et al. AXL targeting abrogates autophagic flux and induces immunogenic cell death in drug-resistant cancer cells[J]. J Thorac Oncol, 2020, 15(6): 973-999.
41	NILSSON M B, SUN H Y, ROBICHAUX J, et al. A YAP/FOXM1 axis mediates EMT-associated EGFR inhibitor resistance and increased expression of spindle assembly checkpoint components[J]. Sci Transl Med, 2020, 12(559): eaaz4589.
42	KURPPA K J, LIU Y, TO C, et al. Treatment-induced tumor dormancy through YAP-mediated transcriptional reprogramming of the apoptotic pathway[J]. Cancer Cell, 2020, 37(1): 104-122.e12.
43	WANG L H, DONG X Y, REN Y, et al. Targeting EHMT2 reverses EGFR-TKI resistance in NSCLC by epigenetically regulating the PTEN/AKT signaling pathway[J]. Cell Death Dis, 2018, 9(2): 129.
44	NAKAGAWA T, TAKEUCHI S, YAMADA T, et al. EGFR-TKI resistance due to BIM polymorphism can be circumvented in combination with HDAC inhibition[J]. Cancer Res, 2013, 73(8): 2428-2434.
45	PERALTA-ARRIETA I, TREJO-VILLEGAS O A, ARMAS-LÓPEZ L, et al. Failure to EGFR-TKI-based therapy and tumoural progression are promoted by MEOX2/GLI1-mediated epigenetic regulation of EGFR in the human lung cancer[J]. Eur J Cancer, 2022, 160: 189-205.
46	YANG L, HE Y T, DONG S, et al. Single-cell transcriptome analysis revealed a suppressive tumor immune microenvironment in EGFR mutant lung adenocarcinoma[J]. J Immunother Cancer, 2022, 10(2): e003534.
47	PENG S L, WANG R, ZHANG X J, et al. EGFR-TKI resistance promotes immune escape in lung cancer via increased PD-L1 expression[J]. Mol Cancer, 2019, 18(1): 165.
48	WU S C, LUO M, TO K K W, et al. Intercellular transfer of exosomal wild type EGFR triggers osimertinib resistance in non-small cell lung cancer[J]. Mol Cancer, 2021, 20(1): 17.
49	SHAH K N, BHATT R, ROTOW J, et al. Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer[J]. Nat Med, 2019, 25(1): 111-118.
50	WANG S H, SONG Y P, LIU D L. EAI045: the fourth-generation EGFR inhibitor overcoming T790M and C797S resistance[J]. Cancer Lett, 2017, 385: 51-54.
51	TO C, JANG J, CHEN T, et al. Single and dual targeting of mutant EGFR with an allosteric inhibitor[J]. Cancer Discov, 2019, 9(7): 926-943.
52	LIU X L, ZHANG X Q, YANG L, et al. Preclinical evaluation of TQB3804, a potent EGFR C797S inhibitor[J]. Cancer Res 2019;79(13).
53	SEQUIST L V, HAN J Y, AHN M J, et al. Osimertinib plus savolitinib in patients with EGFR mutation-positive, MET-amplified, non-small-cell lung cancer after progression on EGFR tyrosine kinase inhibitors: interim results from a multicentre, open-label, phase 1b study[J]. Lancet Oncol, 2020, 21(3): 373-386.
54	YU H A, GOLDBERG S B, LE X N, et al. Biomarker-directed phase Ⅱ platform study in patients with EGFR sensitizing mutation-positive advanced/metastatic non-small cell lung cancer whose disease has progressed on first-line osimertinib therapy (ORCHARD)[J]. Clin Lung Cancer, 2021, 22(6): 601-606.
55	WANG Y B, YANG N, ZHANG Y C, et al. Effective treatment of lung adenocarcinoma harboring EGFR-activating mutation, T790M, and Cis-C797S triple mutations by brigatinib and cetuximab combination therapy[J]. J Thorac Oncol, 2020, 15(8): 1369-1375.
56	LA MONICA S, CRETELLA D, BONELLI M, et al. Trastuzumab emtansine delays and overcomes resistance to the third-generation EGFR-TKI osimertinib in NSCLC EGFR mutated cell lines[J]. J Exp Clin Cancer Res, 2017, 36(1): 174.
57	LE X N, NILSSON M, GOLDMAN J, et al. Dual EGFR-VEGF pathway inhibition: a promising strategy for patients with EGFR-mutant NSCLC[J]. J Thorac Oncol, 2021, 16(2): 205-215.
58	OXNARD G R, YANG J C H, YU H, et al. TATTON: a multi-arm, phase Ⅰb trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer[J]. Ann Oncol, 2020, 31(4): 507-516.
59	SOCINSKI M A, JOTTE R M, CAPPUZZO F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC[J]. N Engl J Med, 2018, 378(24): 2288-2301.
60	ZHANG J, ZHOU C, ZHAO Y, et al. MA11.06 A PII study of toripalimab, a PD-1 MAb, in combination with chemotherapy in EGFR+ advanced NSCLC patients failed to prior EGFR TKI therapies[J]. J Thorac Oncol, 2019, 14(10): S292.
61	BURNETT H, EMICH H, CARROLL C, et al. Epidemiological and clinical burden of EGFR Exon 20 insertion in advanced non-small cell lung cancer: a systematic literature review[J]. PLoS One, 2021, 16(3): e0247620.
62	NORONHA V, CHOUGHULE A, PATIL V, et al. Epidermal growth factor receptor exon 20 mutation in lung cancer: types, incidence, clinical features and impact on treatment[J]. Oncotargets Ther, 2017, 10: 2903-2908.
63	VAN VEGGEL B, DE LANGEN A J, HASHEMI S M S, et al. Afatinib and cetuximab in four patients with EGFR exon 20 insertion-positive advanced NSCLC[J]. J Thorac Oncol, 2018, 13(8): 1222-1226.
64	PARK K, JOHN T, KIM S W, et al. Amivantamab (JNJ-61186372), an anti-EGFR-MET bispecific antibody, in patients with EGFR exon 20 insertion (exon20ins)-mutated non-small cell lung cancer (NSCLC)[J]. J Clin Oncol, 2020, 38(15_suppl): 9512.
65	PARK K, HAURA E B, LEIGHL N B, et al. Amivantamab in EGFR exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS phase Ⅰ study[J]. J Clin Oncol, 2021, 39(30): 3391-3402.
66	CHO B C, LEE K H, CHO E K, et al. 1258O Amivantamab (JNJ-61186372), an EGFR-MET bispecific antibody, in combination with lazertinib, a 3rd-generation tyrosine kinase inhibitor (TKI), in advanced EGFR NSCLC[J]. Ann Oncol, 2020, 31: S813.
67	LE X N, GOLDMAN J, CLARKE J, et al. Abstract CT081: poziotinib activity and durability of responses in previously treated EGFR exon 20 NSCLC patients: a Phase 2 study[C]//Tumor Biology. American Association for Cancer Research, 2020: 80(16).
68	GONZALVEZ F, VINCENT S, BAKER T E, et al. Mobocertinib (TAK-788): a targeted inhibitor of EGFR exon 20 insertion mutants in non-small cell lung cancer[J]. Cancer Discov, 2021, 11(7): 1672-1687.
69	FELIP E, BARLESI F, BESSE B, et al. Phase 2 study of the HSP-90 inhibitor AUY922 in previously treated and molecularly defined patients with advanced non-small cell lung cancer[J]. J Thorac Oncol, 2018, 13(4): 576-584.
70	PARK H R, KIM T M, LEE Y, et al. Acquired resistance to third-generation EGFR tyrosine kinase inhibitors in patients with de novo EGFRT790M-mutant NSCLC[J]. J Thorac Oncol, 2021, 16(11): 1859-1871.
71	ROBICHAUX J P, LE X N, VIJAYAN R S K, et al. Structure-based classification predicts drug response in EGFR-mutant NSCLC[J]. Nature, 2021, 597(7878): 732-737.

[1]	刘子杨, 王小文, 陈力. lncRNA GK-IT1通过调控醛缩酶A影响非小细胞肺癌细胞的恶性进展[J]. 上海交通大学学报（医学版）, 2022, 42(5): 591-601.
[2]	张宇, 吴晓渊, 管丽华, 刘译远, 彭星月, 谢海燕, 胡玮, 郝可可, 夏宁, 陆国军, 侯志波. 高通量药物敏感性筛选系统在非小细胞肺癌伴恶性胸腔积液治疗中的应用[J]. 上海交通大学学报(医学版), 2022, 42(1): 82-89.
[3]	凌徐心仪, 张瑶, 钟华. 非小细胞肺癌免疫治疗获益人群筛选的研究进展[J]. 上海交通大学学报(医学版), 2021, 41(8): 1114-1119.
[4]	马韵芳, 潘丽娜, 李圳, 高蓓莉, 胡家安, 徐志红. 司美替尼下调KRAS G12V突变型非小细胞肺癌细胞PD-L1水平的探索性研究[J]. 上海交通大学学报(医学版), 2021, 41(6): 741-748.
[5]	徐建华, 江萍, 邓炯. ATP结合盒蛋白G超家族成员2在肺癌中的表达及意义[J]. 上海交通大学学报(医学版), 2021, 41(6): 830-833.
[6]	张佳玲, 张凤春, 徐迎春. 乳腺癌脑转移系统治疗的研究进展[J]. 上海交通大学学报(医学版), 2021, 41(5): 671-677.
[7]	郝艳云, 俞思慧, 陆静, 顾湘, 张帆, 程金科, 王田实. SIRT3去SUMO化修饰调节乳腺癌细胞MCF7增殖及化疗药物敏感性的研究[J]. 上海交通大学学报(医学版), 2021, 41(12): 1557-1563.
[8]	王钰婷1, 2，刘锦燕2，史册1，赵珺涛1, 2，项明洁1, 2. 白念珠菌ERG3基因敲除及其对耐药性的影响[J]. 上海交通大学学报（医学版）, 2020, 40(2): 163-.
[9]	陆裕杰，金泽宇，李亚芬，沈坤炜，陈伟国，陈小松. 乳腺癌局部区域复发病灶受体状态检测及对后续治疗的指导价值[J]. 上海交通大学学报（医学版）, 2019, 39(9): 1071-.
[10]	吕霖，石鑫，郭晓奎，秦金红. 耐药肺炎克雷伯菌噬菌体JD902的分离及生物学特性和安全性研究[J]. 上海交通大学学报（医学版）, 2019, 39(12): 1389-.
[11]	屈国君 1，陆元凤 2，李宇 1. PDGFRα下游新底物 CCT2对肿瘤细胞生长的影响及其机制[J]. 上海交通大学学报（医学版）, 2019, 39(1): 28-.
[12]	曹淑慧，周严，李静文，钟华. DCVAC/LuCa联合化疗治疗晚期非小细胞肺癌安全性的探讨[J]. 上海交通大学学报（医学版）, 2018, 38(8): 923-.
[13]	何亚平 1，楼玮群 2，陈杰灵 2，周箴 3，朱静芬 1，简红 3. 病程12个月及以上非小细胞肺癌患者生活质量评估及影响因素研究[J]. 上海交通大学学报（医学版）, 2018, 38(7): 775-.
[14]	刘洋,郑丹丹,韩逸超,史玮炀,戴尔宽,李敏,郑冰 . 多重耐药肺炎克雷伯菌感染的危险因素及治疗方案比较[J]. 上海交通大学学报（医学版）, 2017, 37(7): 973-.
[15]	胡章国，曹淑慧，钟华 . EGFR-TKI 对少见EGFR 21L861Q 突变的晚期非小细胞肺癌患者的治疗效果[J]. 上海交通大学学报（医学版）, 2017, 37(11): 1524-.

非小细胞肺癌第三代表皮生长因子受体-酪氨酸激酶抑制剂的耐药机制及治疗策略

Resistance mechanisms and overcoming strategies of the third-generation EGFR-TKI in non-small cell lung cancer

RichHTML

PDF (PC)

可视化

摘要/Abstract

引用本文

使用本文

图/表 1

参考文献 71

相关文章 15

编辑推荐

Metrics