EGFR/TP53/RB1三重突变的小细胞肺癌转化研究及治疗进展

金倩晨; 王若雨; 王刚; 姜佳宁; 张茹; 陈雯婷; 李佳默; 吕金燕

doi:10.12354/j.issn.1000-8179.2021.20201686

EGFR/TP53/RB1三重突变的小细胞肺癌转化研究及治疗进展

doi: 10.12354/j.issn.1000-8179.2021.20201686

大连大学附属中山医院肿瘤内科（辽宁省大连市 116000）

详细信息

作者简介:
金倩晨：专业方向为肺癌放射治疗及靶向综合治疗

通讯作者:
吕金燕　Lvjinyan312@163.com

计量
- 文章访问数: 977
- HTML全文浏览量: 29
- PDF下载量: 108
- 被引次数: 0
出版历程
- 收稿日期: 2020-12-18
- 刊出日期: 2021-09-14

Advances in translational research and treatment of small cell lung cancer withEGFR/TP53/RB1 triple mutation

Department of Oncology, Affiliated Zhongshan Hospital of Dalian University, Dalian 116000, China

More Information

Corresponding author: Jinyan Lv; E-mail: Lvjinyan312@163.com

摘要

摘要: 表皮生长因子受体（epidermal growth factor receptor，EGFR）突变型非小细胞肺癌（non-small cell lung cancer，NSCLC）患者在接受EGFR酪氨酸激酶抑制剂（tyrosine kinase inhibitors, TKIs ）靶向治疗后能获得临床获益，但之后会不可避免地出现获得性耐药，而发生小细胞肺癌（small cell lung cancer，SCLC）组织学转化被认为是一种罕见的耐药机制。随着二代基因检测（next- generation sequencing，NGS）技术的快速发展及广泛应用，研究者发现存在EGFR/TP53/RB1三重突变的NSCLC经靶向治疗后更容易发生SCLC组织学转化，并且转化型SCLC疗效及预后较差。本文对近年来关于EGFR突变的NSCLC发生SCLC组织学转化的研究作一综述，涉及相关的转化机制、可能有效的新型药物及治疗策略，为EGFR/TP53/RB1三重突变的转化型SCLC患者提供更多潜在的临床治疗选择。
- TP53 /
- RB1 /
- 三重突变 /
- 小细胞肺癌
Abstract: Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) have substantial clinical benefits after treatment with EGFR tyrosine kinase inhibitors (TKIs). However, acquired drug resistance is expected to inevitably develop, and histological transformation to small cell lung cancer (SCLC) is considered a rare mechanism of acquired drug resistance. Considering the wide application and rapid development of next-generation sequencing (NGS), researchers have found that the histological type of EGFR/TP53/RB1 triple mutation in NSCLC is more likely to transform into SCLC after completing targeted therapy. This is particularly worrisome because poor therapeutic efficacy and prognosis are crucial characteristics of transformed SCLC. Thus, in this review, recent studies on the histological transformation of SCLC in patients with EGFR-mutated NSCLC, including those on related transformation mechanisms and novel drugs and treatment strategies, were summarized to provide more potential treatment options for patients with EGFR/TP53/RB1 triple mutation-transformed SCLC.
- TP53 /
- RB1 /
- triple mutations /
- small cell lung cancer (SCLC)

HTML全文

参考文献(35)

[1]	Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2021[J]. CA Cancer J Clin, 2021, 71(1):7-33. doi: 10.3322/caac.21654
[2]	Jordan EJ, Kim HR, Arcila ME, et al. Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies[J]. Cancer Discov, 2017, 7(6):596-609. doi: 10.1158/2159-8290.CD-16-1337
[3]	Shaurova T, Zhang L, 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
[4]	Sequist LV, Waltman BA, Dias-santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors[J]. Sci Transl Med, 2011, 3(75):75ra26.
[5]	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(8):2240-2247. doi: 10.1158/1078-0432.CCR-12-2246
[6]	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
[7]	Molina-Vila MA, Bertran-alamillo J, Gascó A, et al. Nondisruptive p53 mutations are associated with shorter survival in patients with advanced non-small cell lung cancer[J]. Clin Cancer Res, 2014, 20(17):4647-4659. doi: 10.1158/1078-0432.CCR-13-2391
[8]	Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use[J]. Cold Spring Harb Perspect Biol, 2010, 2(1):a001008.
[9]	Poeta ML, Manola J, Goldwasser MA, et al. TP53 mutations and survival in squamous-cell carcinoma of the head and neck[J]. N Engl J Med, 2007, 357(25):2552-2561. doi: 10.1056/NEJMoa073770
[10]	Brosh R, Rotter V. When mutants gain new powers: news from the mutant p53 field[J]. Nat Rev Cancer, 2009, 9(10):701-713. doi: 10.1038/nrc2693
[11]	Muller PA, Vousden KH. p53 mutations in cancer[J]. Nat Cell Biol, 2013, 15(1):2-8. doi: 10.1038/ncb2641
[12]	Wilkie M, Lau A, Vlatkovic N, et al. Tumour metabolism in squamous cell carcinoma of the head and neck: an in-vitro study of the consequences of TP53 mutation and therapeutic implications[J]. Lancet, 2015, 385 (Suppl 1):S101.
[13]	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
[14]	Kareta MS, Gorges LL, Hafeez S, et al. Inhibition of pluripotency networks by the Rb tumor suppressor restricts reprogramming and tumorigenesis[J]. Cell Stem Cell, 2015, 16(1):39-50. doi: 10.1016/j.stem.2014.10.019
[15]	Yu HA, Suzawa K, Jordan E, et al. Concurrent Alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance[J]. Clin Cancer Res, 2018, 24(13):3108-3118. doi: 10.1158/1078-0432.CCR-17-2961
[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]	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, 6:6377. doi: 10.1038/ncomms7377
[18]	Ogino A, Choi J, Lin M, et al. Genomic and pathological heterogeneity in clinically diagnosed small cell lung cancer in never/light smokers identifies therapeutically targetable alterations[J]. Mol Oncol, 2021, 15(1):27-42. doi: 10.1002/1878-0261.12673
[19]	Xie T, Li Y, Ying J, et al. Whole exome sequencing (WES) analysis of transformed small cell lung cancer (SCLC) from lung adenocarcinoma (LUAD)[J]. Transl Lung Cancer Res, 2020, 9(6):2428-2439. doi: 10.21037/tlcr-20-1278
[20]	Lee JK, Lee J, Kim S, et al. Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas[J]. J Clin Oncol, 2017, 35(26):3065-3074. doi: 10.1200/JCO.2016.71.9096
[21]	Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer[J]. N Engl J Med, 2018, 379(23):2220-2229. doi: 10.1056/NEJMoa1809064
[22]	Goldman JW, Garassino MC, Chen Y, et al. Patient-reported outcomes with first-line durvalumab plus platinum-etoposide versus platinum-etoposide in extensive-stage small-cell lung cancer (CASPIAN): a randomized, controlled, open-label, phase III study[J]. Lung Cancer, 2020, 149:46-52. doi: 10.1016/j.lungcan.2020.09.003
[23]	Shoemaker AR, Mitten MJ, Adickes J, et al. Activity of the Bcl-2 family inhibitor ABT-263 in a panel of small cell lung cancer xenograft models[J]. Clin Cancer Res, 2008, 14(11):3268-3277. doi: 10.1158/1078-0432.CCR-07-4622
[24]	Park JW, Lee JK, Sheu KM, et al. Reprogramming normal human epithelial tissues to a common, lethal neuroendocrine cancer lineage[J]. Science, 2018, 362(6410):91-95. doi: 10.1126/science.aat5749
[25]	Witkiewicz AK, Chung S, Brough R, et al. Targeting the vulnerability of rb tumor suppressor loss in triple-negative breast cancer[J]. Cell Rep, 2018, 22(5):1185-1199. doi: 10.1016/j.celrep.2018.01.022
[26]	Shah KN, 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. doi: 10.1038/s41591-018-0264-7
[27]	Oser MG, Fonseca R, Chakraborty AA, et al. Cells lacking the RB1 tumor suppressor gene are hyperdependent on aurora B kinase for survival[J]. Cancer Discov, 2019, 9(2):230-247. doi: 10.1158/2159-8290.CD-18-0389
[28]	Gong X, Du J, Parsons SH, et al. Aurora A kinase inhibition is synthetic lethal with loss of the RB1 tumor suppressor gene[J]. Cancer Discov, 2019, 9(2):248-263. doi: 10.1158/2159-8290.CD-18-0469
[29]	Ku SY, Rosario S, Wang Y, et al. Rb1 and Tp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance[J]. Science, 2017, 355(6320):78-83. doi: 10.1126/science.aah4199
[30]	Ishak CA, Marshall AE, Passos DT, et al. An RB-EZH2 complex mediates silencing of repetitive DNA sequences[J]. Mol Cell, 2016, 64(6):1074-1087. doi: 10.1016/j.molcel.2016.10.021
[31]	Matsumura Y, Umemura S, Ishii G, et al. Expression profiling of receptor tyrosine kinases in high-grade neuroendocrine carcinoma of the lung: a comparative analysis with adenocarcinoma and squamous cell carcinoma[J]. J Cancer Res Clin Oncol, 2015, 141(12):2159-2170. doi: 10.1007/s00432-015-1989-z
[32]	Byers LA, Wang J, Nilsson MB, et al. Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1[J]. Cancer Discov, 2012, 2(9):798-811. doi: 10.1158/2159-8290.CD-12-0112
[33]	Peifer M, Fernández-cuesta L, Sos ML, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer[J]. Nat Genet, 2012, 44(10):1104-1110. doi: 10.1038/ng.2396
[34]	Capozzi M, Cvona, Cded, et al. Antiangiogenic therapy in pancreatic neuroendocrine tumors[J]. Anticancer Res, 2016, 36(10):5025-5030. doi: 10.21873/anticanres.11071
[35]	Wagener-ryczek S, Heydt C, Süptitz J, et al. Mutational spectrum of acquired resistance to reversible versus irreversible EGFR tyrosine kinase inhibitors[J]. BMC Cancer, 2020, 20(1):408. doi: 10.1186/s12885-020-06920-3