EGFR基因突变靶向耐药后小细胞肺癌转化的研究进展

doi:10.3760/cma.j.cn371439-20240328-00120

摘要/Abstract

摘要：

表皮生长因子受体酪氨酸酶抑制剂（EGFR-TKI）的问世为EGFR基因突变患者带来了福音，不仅可以提高患者的生命质量，而且能够延长多数患者的生存期。但这些患者在服用EGFR-TKI 1年左右便会产生耐药，从而导致疾病进展。EGFR-TKI耐药的机制之一为非小细胞肺癌（NSCLC）转化为小细胞肺癌（SCLC），发生率为2%~14%，是一种较为少见的耐药机制。目前，SCLC转化的机制尚不明确，NSCLC向SCLC转化患者的中位生存期大约为17.8个月。研究EGFR-TKI耐药机制、转化型SCLC发生机制及临床特征，对转化型SCLC的治疗方案及预后具有重要意义。

关键词: EGFR突变, 分子靶向治疗, 耐药, 小细胞肺癌, 转化

Abstract:

The advent of epidermal growth factor receptor tyrosine kinase inhibitors （EGFR-TKIs） have brought benefits to patients with EGFR gene mutations， which can not only improve the quality of life of patients， but also prolong their survival. However， most patients develop resistance to EGFR-TKIs after taking them for about one year， leading to disease progression. One of the mechanisms of EGFR-TKIs resistance is the conversion from non-small cell lung cancer （NSCLC） to small cell lung cancer （SCLC）， with an incidence of 2%-14%， which is a relatively rare resistance mechanism. Currently， the mechanism of SCLS transformation remains unclear， and the median survival of patients with NSCLC converted to SCLC is approximately 17.8 months. Studying the resistance mechanism of EGFR-TKIs， the occurrence mechanism and clinical characteristics of transformed SCLC is of great significance for the treatment plan and prognosis of transformed SCLC.

Key words: EGFR mutation, Molecular targeted therapy, Drug resistance, Small cell lung carcinoma, Transformation

赵红晓, 刘春玲. EGFR基因突变靶向耐药后小细胞肺癌转化的研究进展[J]. 国际肿瘤学杂志, 2024, 51(11): 712-716.

Zhao Hongxiao, Liu Chunling. Research progress in the transformation of small cell lung cancer after targeted drug resistance by EGFR gene mutations[J]. Journal of International Oncology, 2024, 51(11): 712-716.

参考文献 34

[1]	Tomic K, Krpina K, Baticic L, et al. Comprehensive molecular and clinical insights into non-small cell lung cancer transformation to small cell lung cancer with an illustrative case report[J]. J Drug Target, 2024, 32(5): 499-509. DOI: 10.1080/1061186x.2024.2332733.
[2]	Chai X, Zhang X, Li W, et al. Small cell lung cancer transformation during antitumor therapies: a systematic review[J]. Open Med (Wars), 2021, 16(1): 1160-1167. DOI: 10.1515/med-2021-0321.
[3]	张碧霞, 丁江华. EGFR突变型非小细胞肺癌EGFR-TKI获得性耐药后免疫治疗现状[J]. 国际肿瘤学杂志, 2023, 50(2): 97-101. DOI: 10.3760/cma.j.cn371439-20220719-00020.
[4]	Shi K, Wang G, Pei J, et al. Emerging strategies to overcome resistance to third-generation EGFR inhibitors[J]. J Hematol Oncol, 2022, 15(1): 94. DOI: 10.1186/s13045-022-01311-6.
[5]	Zakowski MF, Ladanyi M, Kris MG, et al. EGFR mutations in small-cell lung cancers in patients who have never smoked[J]. N Engl J Med, 2006, 355(2): 213-215. DOI: 10.1056/nejmc053610.
[6]	Zhang B, Lewis W, Stewart CA, et al. Brief report: comprehensive clinicogenomic profiling of small cell transformation from EGFR-mutant NSCLC informs potential therapeutic targets[J]. JTO Clin Res Rep, 2023, 5(2): 100623. DOI: 10.1016/j.jtocrr.2023.100623.
[7]	Shaurova T, Zhang LT, Goodrich DW, et al. Understanding lineage plasticity as a path to targeted therapy failure in EGFR-mutant non-small cell lung cancer[J]. Front Genet, 2020, 11: 281. DOI: 10.3389/fgene.2020.00281. pmid: 32292420
[8]	黄珺霞, 王红. 表皮生长因子受体基因突变非小细胞肺癌的靶向治疗及其耐药机制[J]. 中国肺癌杂志, 2022, 25(3): 183-192. DOI: 10.3779/j.issn.1009-3419.2022.101.05.
[9]	Sun R, Hou Z, Zhang Y, et al. Drug resistance mechanisms and progress in the treatment of EGFR-mutated lung adenocarcinoma[J]. Oncol Lett, 2022, 24(5): 408. DOI: 10.3892/ol.2022.13528. pmid: 36245822
[10]	He J, Huang Z, Han L, et al. Mechanisms and management of 3rd‑generation EGFR‑TKI resistance in advanced non‑small cell lung cancer(Review)[J]. Int J Oncol, 2021, 59(5): 90. DOI: 10.3892/ijo.2021.5270.
[11]	Jing M, He X, Cai CZ, et al. Epidermal growth factor receptor regulates lineage plasticity driving transformation to small cell lung cancer[J]. Biochem Biophys Res Commun, 2023, 681: 218-224. DOI: 10.1016/j.bbrc.2023.09.047.
[12]	Chen YX, He MY, Dai ZF, et al. Clinical and molecular profiling of EGFR-mutant lung adenocarcinomas transformation to small cell lung cancer during TKI treatment[J]. Front Oncol, 2023, 13: 1308313. DOI: 10.3389/fonc.2023.1308313.
[13]	Liu YY. Small cell lung cancer transformation from EGFR-mutated lung adenocarcinoma: a case report and literatures review[J]. Cancer Biol Ther, 2018, 19(6): 445-449. DOI: 10.1080/15384047.2018.1435222. pmid: 29461911
[14]	Rath B, Plangger A, Hamilton G. Non-small cell lung cancer-small cell lung cancer transformation as mechanism of resistance to tyrosine kinase inhibitors in lung cancer[J]. Cancer Drug Resist, 2020, 3(2): 171-178. DOI: 10.20517/cdr.2019.85. pmid: 35582610
[15]	Yin XM, Li YY, Wang H, et al. Small cell lung cancer transformation: from pathogenesis to treatment[J]. Semin Cancer Biol, 2022, 86(Pt 2): 595-606. DOI: 10.1016/j.semcancer.2022.03.006. pmid: 35276343
[16]	Offin M, Chan JM, Tenet M, et al. Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes[J]. J Thorac Oncol, 2019, 14(10): 1784-1793. DOI: 10.1016/j.jtho.2019.06.002.
[17]	Hao L, Chen H, Wang L, et al. Transformation or tumor heterogeneity: mutations in EGFR, SOX2, TP53, and RB1 persist in the histological rapid conversion from lung adenocarcinoma to small-cell lung cancer[J]. Thorac Cancer, 2023, 14(11): 1036-1041. DOI: 10.1111/1759-7714.14832.
[18]	张文秋, 李永琦, 吴荻. 非小细胞肺癌EGFR-TKIs耐药——小细胞肺癌转化的研究进展[J]. 中国肺癌杂志, 2017, 20(10): 720-726. DOI: 10.3779/j.issn.1009-3419.2017.10.10.
[19]	Ferrer L, Giaj Levra M, Brevet M, et al. A brief report of transformation from NSCLC to SCLC: molecular and therapeutic characte-ristics[J]. J Thorac Oncol, 2019, 14(1): 130-134. DOI: 10.1016/j.jtho.2018.08.2028.
[20]	Wang W, Xu C, Chen H, et al. Genomic alterations and clinical outcomes in patients with lung adenocarcinoma with transformation to small cell lung cancer after treatment with EGFR tyrosine kinase inhibitors: a multicenter retrospective study[J]. Lung Cancer, 2021, 155: 20-27. DOI: 10.1016/j.lungcan.2021.03.006. pmid: 33714778
[21]	Liu H, Chen LH, Zhang ZH, et al. Histomorphological transformation from non-small cell lung carcinoma to small cell lung carcinoma after targeted therapy or immunotherapy: a report of two cases[J]. Front Oncol, 2022, 12: 1022705. DOI: 10.3389/fonc.2022.1022705.
[22]	Xie Z, Gu Y, Lin X, et al. Unexpected favorable outcome to etoposide and cisplatin in a small cell lung cancer transformed patient: a case report[J]. Cancer Biol Ther, 2019, 20(9): 1172-1175. DOI: 10.1080/15384047.2019.1617561. pmid: 31161851
[23]	金倩晨, 王若雨, 王刚, 等. EGFR/TP53/RB1三重突变的小细胞肺癌转化研究及治疗进展[J]. 中国肿瘤临床, 2021, 48(16): 847-851. DOI: 10.12354/j.issn.1000-8179.2021.20201686.
[24]	Wang S, Xie T, Hao X, et al. Comprehensive analysis of treatment modes and clinical outcomes of small cell lung cancer transformed from epidermal growth factor receptor mutant lung adenocarcinoma[J]. Thorac Cancer, 2021, 12(19): 2585-2593. DOI: 10.1111/1759-7714.14144. pmid: 34490724
[25]	Tenjin Y, Nakamura K, Ishizuka S, et al. Small cell lung cancer derived from adenocarcinoma with mutant epidermal growth factor receptor provides a signature of transcriptional alteration in tumor cells[J]. Intern Med, 2019, 58(22): 3261-3265. DOI: 10.2169/internalmedicine.2988-19.
[26]	Schaefer T, Lengerke C. SOX2 protein biochemistry in stemness, reprogramming, and cancer: the PI3K/AKT/SOX2 axis and beyond[J]. Oncogene, 2020, 39(2): 278-292. DOI: 10.1038/s41388-019-0997-x. pmid: 31477842
[27]	Quintanal-Villalonga A, Taniguchi H, Zhan YA, et al. Multiomic analysis of lung tumors defines pathways activated in neuroendocrine transformation[J]. Cancer Discov, 2021, 11(12): 3028-3047. DOI: 10.1158/2159-8290.cd-20-1863. pmid: 34155000
[28]	Niederst MJ, Sequist LV, Poirier JT, et al. RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer[J]. Nat Commun, 2015, 6(1): 6377. DOI: 10.1038/ncomms7377.
[29]	Knudsen ES, Pruitt SC, Hershberger PA, et al. Cell cycle and beyond: exploiting new RB1 controlled mechanisms for cancer therapy[J]. Trends Cancer, 2019, 5(5): 308-324. DOI: 10.1016/j.trecan.2019.03.005. pmid: 31174843
[30]	Xu J, Xu L, Wang B, et al. Outcomes in patients with lung adenocarcinoma with transformation to small cell lung cancer after EGFR tyrosine kinase inhibitors resistance: a systematic review and pooled analysis[J]. Front Oncol, 2022, 11: 766148. DOI: 10.3389/fonc.2021.766148.
[31]	Leonetti A, Minari R, Mazzaschi G, et al. Small cell lung cancer transformation as a resistance mechanism to osimertinib in epidermal growth factor receptor-mutated lung adenocarcinoma: case report and literature review[J]. Front Oncol, 2021, 11: 642190. DOI: 10.3389/fonc.2021.642190.
[32]	Marcoux N, Gettinger SN, 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. DOI: 10.1200/jco.18.01585. pmid: 30550363
[33]	吴洁琼, 任敦强, 易冰倩, 等. 晚期肺腺癌靶向耐药后小细胞癌转化2例并文献复习[J]. 中国肺癌杂志, 2022, 25(11): 828-834. DOI: 10.3779/j.issn.1009-3419.2022.102.41.
[34]	Lai L, Meng W, Wei J, et al. Transformation of NSCLC to SCLC after 1st- and 3rd-generation EGFR-TKI resistance and response to EP regimen and erlotinib: 2 CARE-compliant case reports[J]. Medicine (Baltimore), 2021, 100(10): e25046. DOI: 10.1097/md.0000000000025046.