非小细胞肺癌表皮生长因子受体靶向治疗的研究进展

doi:10.3969/j.issn.1006-5725.2024.15.021

Abstract

Abstract:

Lung cancer is the most fatal malignant tumor worldwide， with non-small cell lung cancer （NSCLC） being the predominant pathological subtype. The development of NSCLC is driven by mutations in the epidermal growth factor receptor （EGFR）， and EGFR tyrosine kinase inhibitors （EGFR-TKIs） are employed as targeted therapies for first-line treatment of advanced NSCLC patients harboring EGFR mutations. However， variations in molecular structures， concurrent mutations， and mechanisms of therapeutic resistance contribute to prognostic disparities among different EGFR subgroups. This review primarily summarizes the molecular structural basis and differential treatment responses associated with distinct types of EGFR mutations in NSCLC.

Key words: non-small cell lung cancer, EGFR mutations, targeted therapy, molecular structure

CLC Number:

R734.2

Yuting LI,Qilu YAN,Qibin. SONG. Molecular basis of variability in EGFR⁃targeted therapy response in non⁃small cell lung cancer[J]. The Journal of Practical Medicine, 2024, 40(15): 2166-2171.

References 51

1	SIEGEL R L， MILLER K D， WAGLE N S， Jemal A. Cancer statistics， 2023 ［J］. CA Cancer J Clin， 2023， 73（1）： 17-48. doi:10.3322/caac.21763 doi: 10.3322/caac.21763
2	郑荣寿，陈茹，韩冰峰，等. 2022年中国恶性肿瘤流行情况分析［J］. 中华肿瘤杂志， 2024，46（3）：221-231. doi:10.3760/cma.j.cn112152-20240119-00035 doi: 10.3760/cma.j.cn112152-20240119-00035
3	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. doi:10.3322/caac.21660 doi: 10.3322/caac.21660
4	ETTINGER D S， WOOD D E， AISNER D L， et al. NCCN Guidelines（R） Insights： Non-Small Cell Lung Cancer， Version 2.2023 ［J］. J Natl Compr Canc Netw， 2023， 21（4）： 340-350.
5	LIU W J， DU Y， WEN R， et al. Drug resistance to targeted therapeutic strategies in non-small cell lung cancer ［J］. Pharmacol Ther， 2020， 206： 107438. doi:10.1016/j.pharmthera.2019.107438 doi: 10.1016/j.pharmthera.2019.107438
6	BRAZEL D， KROENING G， NAGASAKA M. Non-small Cell Lung Cancer with EGFR or HER2 Exon 20 Insertion Mutations： Diagnosis and Treatment Options ［J］. BioDrugs， 2022， 36（6）： 717-729. doi:10.1007/s40259-022-00556-4 doi: 10.1007/s40259-022-00556-4
7	崔久嵬，段建春，任胜祥，等. 三代EGFR-TKI在EGFR突变NSCLC治疗中应用的专家共识（2022年版）［J］. 中国肺癌杂志， 2022， 25（9）： 627-641.
8	TAMIRAT M Z， KOIVU M， ELENIUS K， et al. Structural characterization of EGFR exon 19 deletion mutation using molecular dynamics simulation ［J］. PLoS One， 2019， 14（9）： e0222814. doi:10.1371/journal.pone.0222814 doi: 10.1371/journal.pone.0222814
9	DU Z， BROWN B P， KIM S， et al. Structure-function analysis of oncogenic EGFR Kinase Domain Duplication reveals insights into activation and a potential approach for therapeutic targeting ［J］. Nat Commun， 2021， 12（1）： 1382. doi:10.1038/s41467-021-21613-6 doi: 10.1038/s41467-021-21613-6
10	SABBAH D A， HAJJO R， SWEIDAN K. Review on Epidermal Growth Factor Receptor （EGFR） Structure， Signaling Pathways， Interactions， and Recent Updates of EGFR Inhibitors ［J］. Curr Top Med Chem， 2020， 20（10）： 815-834. doi:10.2174/1568026620666200303123102 doi: 10.2174/1568026620666200303123102
11	LI W Q， CUI J W. Non-small cell lung cancer patients with ex19del or exon 21 L858R mutation： distinct mechanisms， different efficacies to treatments ［J］. J Cancer Res Clin Oncol， 2020， 146（9）： 2329-2338. doi:10.1007/s00432-020-03296-6 doi: 10.1007/s00432-020-03296-6
12	LE X， 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. doi:10.1016/j.jtho.2020.10.006 doi: 10.1016/j.jtho.2020.10.006
13	LEVANTINI E， MARONI G， DEL RE M， et al. EGFR signaling pathway as therapeutic target in human cancers ［J］. Semin Cancer Biol， 2022， 85： 253-275. doi:10.1016/j.semcancer.2022.04.002 doi: 10.1016/j.semcancer.2022.04.002
14	CHEN P， LIU Y， WEN Y， et al. Non-small cell lung cancer in China ［J］. Cancer Commun （Lond）， 2022， 42（10）： 937-970. doi:10.1002/cac2.12359 doi: 10.1002/cac2.12359
15	王延贺，黄立娜，张玉文. 河南豫东地区661例非小细胞肺癌常见驱动基因突变分析［J］. 实用医学杂志， 2024， 40（1）： 38-42.
16	CHEN H， HU S， PATTERSON A V， et al. Structural Mechanism and Inhibitors Targeting EGFR Exon 20 Insertion （Ex20ins） Mutations ［J］. J Med Chem， 2023， 66（17）： 11656-11671. doi:10.1021/acs.jmedchem.3c00875 doi: 10.1021/acs.jmedchem.3c00875
17	GEORGE S L. Selection bias， phase II trials， and the FDA accelerated approval process ［J］. J Natl Cancer Inst， 2003， 95（18）： 1351-1352. doi:10.1093/jnci/djg070 doi: 10.1093/jnci/djg070
18	BATRA U， BISWAS B， PRABHASH K， et al. Differential clinicopathological features， treatments and outcomes in patients with Exon 19 deletion and Exon 21 L858R EGFR mutation-positive adenocarcinoma non-small-cell lung cancer ［J］. BMJ Open Respir Res， 2023， 10（1）：e001492. doi:10.1136/bmjresp-2022-001492 doi: 10.1136/bmjresp-2022-001492
19	顾艳斐，田笑如，王若天，等. 奥希替尼联合贝伐珠单抗在获得性EGFR T790M突变晚期非小细胞肺癌的疗效分析［J］. 中国肺癌杂志， 2022， 25（12）： 843-851. doi:10.3779/j.issn.1009-3419.2022.101.56 doi: 10.3779/j.issn.1009-3419.2022.101.56
20	INUKAI M， TOYOOKA S， ITO S， et al. Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer ［J］. Cancer Res， 2006， 66（16）： 7854-7858. doi:10.1158/0008-5472.can-06-1951 doi: 10.1158/0008-5472.can-06-1951
21	TAN L， BROWN C， MERSIADES A， et al. A Phase II trial of alternating osimertinib and gefitinib therapy in advanced EGFR-T790M positive non-small cell lung cancer： OSCILLATE ［J］. Nat Commun， 2024， 15（1）： 1823. doi:10.1038/s41467-024-46008-1 doi: 10.1038/s41467-024-46008-1
22	BORGEAUD M， PARIKH K， BANNA G L， et al. Unveiling the Landscape of Uncommon EGFR Mutations in NSCLC-A Systematic Review ［J］. J Thorac Oncol， 2024， doi： 10.1016/j.jtho. 2024.03.016 . doi: 10.1016/j.jtho. 2024.03.016
23	BAI Q， WANG J， ZHOU X. EGFR exon20 insertion mutations in non-small cell lung cancer： Clinical implications and recent advances in targeted therapies ［J］. Cancer Treat Rev， 2023， 120： 102605. doi:10.1016/j.ctrv.2023.102605 doi: 10.1016/j.ctrv.2023.102605
24	ELAMIN Y Y， ROBICHAUX J P， CARTER B W， et al. Poziotinib for EGFR exon 20-mutant NSCLC： Clinical efficacy， resistance mechanisms， and impact of insertion location on drug sensitivity ［J］. Cancer Cell， 2022， 40（7）： 754-767.e6. doi:10.1016/j.ccell.2022.06.006 doi: 10.1016/j.ccell.2022.06.006
25	HONG S， GAO F， FU S， et al. Concomitant Genetic Alterations With Response to Treatment and Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients With EGFR-Mutant Advanced Non-Small Cell Lung Cancer ［J］. JAMA Oncol， 2018， 4（5）： 739-742. doi:10.1001/jamaoncol.2018.0049 doi: 10.1001/jamaoncol.2018.0049
26	HEPPNER D E， GUNTHER M， WITTLINGER F， et al. Structural Basis for EGFR Mutant Inhibition by Trisubstituted Imidazole Inhibitors ［J］. J Med Chem， 2020， 63（8）： 4293-4305. doi:10.1021/acs.jmedchem.0c00200 doi: 10.1021/acs.jmedchem.0c00200
27	ZHU J Q， ZHONG W Z， ZHANG G C， et al. Better survival with EGFR exon 19 than exon 21 mutations in gefitinib-treated non-small cell lung cancer patients is due to differential inhibition of downstream signals ［J］. Cancer Lett， 2008， 265（2）： 307-317. doi:10.1016/j.canlet.2008.02.064 doi: 10.1016/j.canlet.2008.02.064
28	HONG W， WU Q， ZHANG J，et al. Prognostic value of EGFR 19-del and 21-L858R mutations in patients with non-small cell lung cancer ［J］. Oncol Lett， 2019， 18（4）： 3887-3895.
29	SORIA J C， OHE Y， VANSTEENKISTE J， et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer ［J］. N Engl J Med， 2018， 378（2）： 113-125. doi:10.1056/nejmoa1713137 doi: 10.1056/nejmoa1713137
30	LI H， WANG J， ZHANG G， et al. Detection of plasma T790M mutation after the first generation EGFR-TKI resistance of non-small cell lung cancer in the real world ［J］. J Thorac Dis， 2020， 12（3）： 550-557. doi:10.21037/jtd.2019.12.122 doi: 10.21037/jtd.2019.12.122
31	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. doi:10.1056/nejmoa1913662 doi: 10.1056/nejmoa1913662
32	OXNARD G R， ARCILA M E， SIMA C S， et al. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer： distinct natural history of patients with tumors harboring the T790M mutation ［J］. Clin Cancer Res， 2011， 17（6）： 1616-1622. doi:10.1158/1078-0432.ccr-10-2692 doi: 10.1158/1078-0432.ccr-10-2692
33	WU S G， LIU Y N， TSAI M F， et al. The mechanism of acquired resistance to irreversible EGFR tyrosine kinase inhibitor-afatinib in lung adenocarcinoma patients ［J］. Oncotarget， 2016， 7（11）： 12404-12413. doi:10.18632/oncotarget.7189 doi: 10.18632/oncotarget.7189
34	RAMALINGAM S S， YANG J C， LEE C K， et al. Osimertinib As First-Line Treatment of EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer ［J］. J Clin Oncol， 2018， 36（9）： 841-849. doi:10.1200/jco.2017.74.7576 doi: 10.1200/jco.2017.74.7576
35	CHO B C， AHN M J， KANG J H， et al. Lazertinib Versus Gefitinib as First-Line Treatment in Patients With EGFR-Mutated Advanced Non-Small-Cell Lung Cancer： Results From LASER301 ［J］. J Clin Oncol， 2023， 41（26）： 4208-4217. doi:10.1200/jco.23.00515 doi: 10.1200/jco.23.00515
36	LU S， ZHOU J， JIAN H， et al. Befotertinib （D-0316） versus icotinib as first-line therapy for patients with EGFR-mutated locally advanced or metastatic non-small-cell lung cancer： a multicentre， open-label， randomised phase 3 study ［J］. Lancet Respir Med， 2023， 11（10）： 905-915. doi:10.1016/s2213-2600(23)00183-2 doi: 10.1016/s2213-2600(23)00183-2
37	THRESS K S， PAWELETZ C P， 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（6）： 560-562. doi:10.1038/nm.3854 doi: 10.1038/nm.3854
38	PIPER-VALLILLO A J， SEQUIST L V， PIOTROWSKA Z. Emerging Treatment Paradigms for EGFR-Mutant Lung Cancers Progressing on Osimertinib： A Review ［J］. J Clin Oncol， 2020， doi： 10.1200/JCO.19.03123 . doi: 10.1200/JCO.19.03123
39	徐越，张言斌，苏珊. 基于转录组测序探究C-MET表达在非小细胞肺癌中的免疫调控机制［J］. 实用医学杂志， 2024， 40（1）： 7-12.
40	ZALAQUETT Z， CATHERINE RITA HACHEM M， KASSIS Y， et al. Acquired resistance mechanisms to osimertinib： The constant battle ［J］. Cancer Treat Rev， 2023， 116： 102557. doi:10.1016/j.ctrv.2023.102557 doi: 10.1016/j.ctrv.2023.102557
41	ENO M S， BRUBAKER J D， CAMPBELL J E， et al. Discovery of BLU-945， a Reversible， Potent， and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer ［J］. J Med Chem， 2022， 65（14）： 9662-9677. doi:10.1021/acs.jmedchem.2c00704 doi: 10.1021/acs.jmedchem.2c00704
42	LIM S M， FUJINO T， KIM C， et al. BBT-176， a Novel Fourth-Generation Tyrosine Kinase Inhibitor for Osimertinib-Resistant EGFR Mutations in Non-Small Cell Lung Cancer ［J］. Clin Cancer Res， 2023， 29（16）： 3004-3016. doi:10.1158/1078-0432.ccr-22-3901 doi: 10.1158/1078-0432.ccr-22-3901
43	ZHU Y， YE X， SHEN H， et al. Discovery of Novel Fourth-Generation EGFR Inhibitors to Overcome C797S-Mediated Resistance ［J］. J Med Chem， 2023， 66（21）： 14633-14652. doi:10.1021/acs.jmedchem.3c01165 doi: 10.1021/acs.jmedchem.3c01165
44	KIM T M， OCK C Y， KIM M， et al. Phase Ⅱ study of osimertinib in NSCLC patients with EGFR exon 20 insertion mutation A multicenter trial of the Korean Cancer Study Group （LU17-19）［J］. Ann Oncol， 2019， 30（）： v628. doi:10.1093/annonc/mdz260.051 doi: 10.1093/annonc/mdz260.051
45	YASUDA H， ICHIHARA E， SAKAKIBARA-KONISHI J， et al. A phase Ⅰ/Ⅱ study of osimertinib in EGFR exon 20 insertion mutation-positive non-small cell lung cancer ［J］. Lung Cancer， 2021， 162： 140-146. doi:10.1016/j.lungcan.2021.10.006 doi: 10.1016/j.lungcan.2021.10.006
46	HAN B， ZHOU C， WU L， et al. Preclinical and preliminary clinical investigations of furmonertinib in NSCLC with EGFR exon 20 insertions （20ins）［J］. Ann Oncol， 2021， 32（）： S949-S1039. doi:10.1016/j.annonc.2021.08.1815 doi: 10.1016/j.annonc.2021.08.1815
47	ZHOU C， RAMALINGAM S S， KIM T M， et al. Treatment Outcomes and Safety of Mobocertinib in Platinum-Pretreated Patients With EGFR Exon 20 Insertion-Positive Metastatic Non-Small Cell Lung Cancer： A Phase 1/2 Open-label Nonrandomized Clinical Trial ［J］. JAMA Oncol， 2021， 7（12）： e214761. doi:10.1001/jamaoncol.2021.4761 doi: 10.1001/jamaoncol.2021.4761
48	MARKHAM A. Mobocertinib： First Approval ［J］. Drugs， 2021， 81（17）： 2069-2074. doi:10.1007/s40265-021-01632-9 doi: 10.1007/s40265-021-01632-9
49	SYED Y Y. Amivantamab： First Approval ［J］. Drugs， 2021， 81（11）： 1349-1353. doi:10.1007/s40265-021-01561-7 doi: 10.1007/s40265-021-01561-7
50	CHON K， LARKINS E， CHATTERJEE S， et al. FDA Approval Summary： Amivantamab for the Treatment of Patients with Non-Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations ［J］. Clin Cancer Res， 2023， 29（17）： 3262-3266. doi:10.1158/1078-0432.ccr-22-3713 doi: 10.1158/1078-0432.ccr-22-3713
51	ZHOU C， TANG K J， CHO B C， et al. Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions ［J］. N Engl J Med， 2023， 389（22）： 2039-2051. doi:10.1056/nejmoa2306441 doi: 10.1056/nejmoa2306441

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Molecular basis of variability in EGFR⁃targeted therapy response in non⁃small cell lung cancer

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