小细胞肺癌的分子生物学研究进展

doi:10.3760/cma.j.issn.1673422X.2018.02.013

摘要/Abstract

摘要： 小细胞肺癌(SCLC)易发生早期复发转移与许多基因改变相关。由DLL3抗体Rovalpituzumab和细胞毒药物Tesirine组成的药物ROVAT通过与DLL3结合后释放Tesirine达到杀伤肿瘤的作用；Nfib通过改变染色体的结构促进SCLC的转移；PRAP、EZH2和Wee1抑制剂通过抑制DNA损伤修复来提高化疗药物的抗肿瘤活性；伊匹单抗和纳武单抗联合用药能够激活人体免疫系统发挥抗肿瘤作用。

关键词: 癌, 小细胞, 免疫疗法, 靶向治疗

Abstract: Small cell lung cancer (SCLC) is typified by early recurrence and metastasis associated with many genetic changes. The drug ROVAT composed of the DLL3 antibody Rovalpituzumab and the cytotoxic drug Tesirine achieves the tumorkilling effect by releasing the Tesirine when bound to DLL3. Nfib promotes the SCLC metastasis by altering the structure of the chromosome. The PRAP, EZH2 and Wee1 inhibitors inhibit the DNA damage repair to improve the antitumor activity of chemotherapeutic drugs. Combination of Ipilimumab and Nivolumab can activate the human immune system to exert antitumor effect.

Key words: Carcinoma, small cell, Immunotherapy, Targeted therapy

孟玲, 魏永长, 谢丛华. 小细胞肺癌的分子生物学研究进展[J]. 国际肿瘤学杂志, 2018, 45(2): 115-118.

MENG Ling, WEI Yong-Chang, XIE Cong-Hua. Molecular biology progress of small cell lung cancer[J]. Journal of International Oncology, 2018, 45(2): 115-118.

参考文献

［1］ Hare F, Giri S, Patel JK, et al. A populationbased analysis of outcomes for small cell carcinoma of the breast by tumor stage and the use of radiation therapy［J］. Springerplus, 2015, 4: 138. DOI: 10.1186/s400640150913y. ［2］ Stone EC, Zhou C, International Association for the Study of Lung Cancer Tobacco Control Committee. Slowing the titanic: China′s epic struggle with tobacco［J］. J Thorac Oncol, 2016, 11(12): 20532065. DOI: 10.1016/J.JTHO.2016.07.020. ［3］ Vanharanta S, Shu W, Brenet F, et al. Epigenetic expansion of VHLHIF signal output drives multiorgan metastasis in renal cancer［J］. Nat Med, 2013, 19(1): 5056. DOI: 10.1038/nm.3029. ［4］ Denny SK, Yang D, Chuang CH, et al. Nfib promotes metastasis through a widespread increase in chromatin accessibility［J］. Cell, 2016, 166(2): 328342. DOI: 10.1016/j.cell.2016.05.052. ［5］ Semenova EA, Kwon MC, Monkhorst K, et al. Transcription factor NFIB is a driver of small cell lung cancer progression in mice and marks metastatic disease in patients［J］. Cell Rep, 2016, 16(3): 631643. DOI: 10.1016/j.celrep.2016.06.020. ［6］ Wu N, Jia D, Ibrahim AH, et al. NFIB overexpression cooperates with Rb/p53 deletion to promote small cell lung cancer［J］. Oncotarget, 2016, 7(36): 5751457524. DOI: 10.18632/oncotarget.11583. ［7］ Heng YH, Zhou B, Harris L, et al. NFIX regulates proliferation and migration within the murine SVZ neurogenic niche［J］. Cereb Cortex, 2015, 25(10): 37583778. DOI: 10.1093/cercor/bhu253. ［8］ Piper M, Barry G, Harvey TJ, et al. NFIBmediated repression of the epigenetic factor Ezh2 regulates cortical development［J］. J Neurosci, 2014, 34(8): 29212930. DOI: 10.1523/JNEUROSCI.231913.2014. ［9］ Hsu YC, Osinski J, Campbell CE, et al. Mesenchymal nuclear factor ⅠB regulates cell proliferation and epithelial differentiation during lung maturation［J］. Dev Biol, 2011, 354(2): 242252. DOI: 10.1016/j.ydbio.2011.04.002. ［10］ Chen KS, Lim JWC, Richards LJ, et al. The convergent roles of the nuclear factor Ⅰ transcription factors in development and cancer［J］. Cancer Lett, 2017, 410: 124138. DOI: 10.1016/j.canlet.2017.09.015. ［11］ Chang CY, Pasolli HA, Giannopoulou EG, et al. NFIB is a governor of epithelialmelanocyte stem cell behaviour in a shared niche［J］. Nature, 2013, 495(7439): 98102. DOI: 10.1038/nature11847. ［12］ Dooley AL, Winslow MM, Chiang DY, et al. Nuclear factor Ⅰ/B is an oncogene in small cell lung cancer［J］. Genes Dev, 2011, 25(14): 14701475. DOI: 10.1101/gad.2046711. ［13］ Sung MH, Baek S, Hager GL. Genomewide footprinting: ready for prime time?［J］. Nat Methods, 2016, 13(3): 222228. DOI: 10.1038/nmeth.3766. ［14］ George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer［J］. Nature, 2015, 524(7563): 4753. DOI: 10.1038/nature14664. ［15］ Saunders LR, Bankovich AJ, Anderson WC, et al. A DLL3targeted antibodydrug conjugate eradicates highgrade pulmonary neuroendocrine tumorinitiating cells in vivo［J］. Sci Transl Med, 2015, 7(302): 302ra136. DOI: 10.1126/scitranslmed.aac9459. ［16］ Rudin CM, Pietanza MC, Bauer TM, et al. Rovalpituzumab tesirine, a DLL3targeted antibodydrug conjugate, in recurrent smallcell lung cancer: a firstinhuman, firstinclass, openlabel, phase 1 study［J］. Lancet Oncol, 2017, 18(1): 4251. DOI: 10.1016/S14702045(16)305654. ［17］ 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. ［18］ Poirier JT, Gardner EE, Connis N, et al. DNA methylation in small cell lung cancer defines distinct disease subtypes and correlates with high expression of EZH2［J］. Oncogene, 2015, 34(48): 58695878. DOI: 10.1038/onc.2015.38. ［19］ Gardner EE, Lok BH, Schneeberger VE, et al. Chemosensitive relapse in small cell lung cancer proceeds through an EZH2SLFN11 axis［J］. Cancer Cell, 2017, 31(2): 286299. DOI: 10.1016/j.ccell.2017.01.006. ［20］ Hirai H, Arai T, Okada M, et al. MK1775, a small molecule Wee1 inhibitor, enhances antitumor efficacy of various DNAdamaging agents, including 5fluorouracil［J］. Cancer Biol Ther, 2010, 9(7): 514522. ［21］ Rajeshkumar NV, De Oliveira E, Ottenhof N, et al. MK1775, a potent Wee1 inhibitor, synergizes with gemcitabine to achieve tumor regressions, selectively in p53deficient pancreatic cancer xenografts［J］. Clin Cancer Res, 2011, 17(9): 27992806. DOI: 10.1158/10780432.CCR102580. ［22］ Guertin AD, Martin MM, Roberts B, et al. Unique functions of CHK1 and WEE1 underlie synergistic antitumor activity upon pharmacologic inhibition［J］. Cancer Cell Int, 2012, 12(1): 45. DOI: 10.1186/147528671245. ［23］ Lal S, Zarei M, Chand SN, et al. WEE1 inhibition in pancreatic cancer cells is dependent on DNA repair status in a context dependent manner［J］. Sci Rep, 2016, 6: 33323. DOI: 10.1038/srep33323. ［24］ Sharma P. Immune checkpoint therapy and the search for predictive biomarkers［J］. Cancer Journal, 2016, 22(2): 68. DOI: 10.1097/PPO.0000000000000185. ［25］ Antonia SJ, LopezMartin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent smallcell lung cancer (CheckMate 032): a multicentre, openlabel, phase 1/2 trial［J］. Lancet Oncol, 2016, 17(7): 883895. DOI: 10.1016/S14702045(16)300985. ［26］ Reck M, Luft A, Szczesna A, et al. Phase Ⅲ randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensivestage smallcell lung cancer［J］. J Clin Oncol, 2016, 34(31): 37403748. DOI: 10.1200/JCO.2016.67.6601. ［27］ Weiskopf K, Jahchan NS, Schnorr PJ, et al. CD47blocking immunotherapies stimulate macrophagemediated destruction of smallcell lung cancer［J］. J Clin Invest, 2016, 126(7): 26102620. DOI: 10.1172/JCI81603. ［28］ Postow MA, Callahan MK, Barker CA, et al. Immunologic correlates of the abscopal effect in a patient with melanoma［J］. N Engl J Med, 2012, 366(10): 925931. DOI: 10.1056/NEJMoa1112824. ［29］ Golden EB, Demaria S, Schiff PB, et al. An abscopal response to radiation and ipilimumab in a patient with metastatic nonsmall cell lung cancer［J］. Cancer Immunol Res, 2013, 1(6): 365372. DOI: 10.1158/23266066.CIR130115.

[1]	钱晓涛, 石子宜, 胡格, 吴晓维. Ⅲ~ⅣA期食管鳞状细胞癌放化疗后行巩固化疗的疗效：一项真实世界临床研究[J]. 国际肿瘤学杂志, 2024, 51(6): 326-331.
[2]	郭泽浩, 张俊旺. PFDN及其亚基在肿瘤发生发展中的作用[J]. 国际肿瘤学杂志, 2024, 51(6): 350-353.
[3]	王盈, 刘楠, 郭兵. 抗体药物偶联物在转移性乳腺癌治疗中的研究进展[J]. 国际肿瘤学杂志, 2024, 51(6): 364-369.
[4]	高凡, 王萍, 杜超, 褚衍六. 肠道菌群与结直肠癌非手术治疗的相关研究进展[J]. 国际肿瘤学杂志, 2024, 51(6): 376-381.
[5]	王丽, 刘志华, 杨伟洪, 蒋凤莲, 李全泳, 宋浩杰, 鞠文东. ROS1突变肺腺鳞癌合并脑梗死为主要表现的Trousseau综合征1例[J]. 国际肿瘤学杂志, 2024, 51(6): 382-384.
[6]	范志鹏, 余静, 胡静, 廖正凯, 徐禹, 欧阳雯, 谢丛华. 炎症标志物的变化趋势对一线接受免疫联合化疗的晚期非小细胞肺癌患者预后的预测价值[J]. 国际肿瘤学杂志, 2024, 51(5): 257-266.
[7]	王俊毅, 洪楷彬, 纪荣佳, 陈大朝. 癌结节对结直肠癌根治性切除术后肝转移的影响[J]. 国际肿瘤学杂志, 2024, 51(5): 280-285.
[8]	顾芳萌, 徐晨阳, 雷大鹏. 人工智能辅助电子喉镜检查在喉癌及喉癌前病变诊治中的研究进展[J]. 国际肿瘤学杂志, 2024, 51(5): 303-307.
[9]	王培鑫, 赵军, 徐世红, 姜朝阳, 王小强, 杨红娟. 铁死亡相关机制在骨肉瘤中的应用进展[J]. 国际肿瘤学杂志, 2024, 51(5): 308-311.
[10]	张文馨, 夏泠, 彭晋, 周福祥. 甲胎蛋白升高型胃肝样腺癌1例并文献复习[J]. 国际肿瘤学杂志, 2024, 51(5): 312-315.
[11]	王昆, 周中新, 臧其威. 血清TGF-β1、VEGF水平对非小细胞肺癌患者单孔胸腔镜根治术后复发的预测价值[J]. 国际肿瘤学杂志, 2024, 51(4): 198-203.
[12]	杨毫, 施贵冬, 张程城, 张跃, 张力文, 付茂勇. 信迪利单抗与替雷利珠单抗在进展期食管鳞状细胞癌新辅助治疗中的疗效及安全性对比[J]. 国际肿瘤学杂志, 2024, 51(4): 210-216.
[13]	姚益新, 沈煜霖. 血清SOCS3、TXNIP水平对肝细胞癌TACE治疗预后的预测价值[J]. 国际肿瘤学杂志, 2024, 51(4): 217-222.
[14]	胡婷婷, 王越华. 电子鼻与线虫鼻——新型早期癌症筛查工具[J]. 国际肿瘤学杂志, 2024, 51(4): 223-226.
[15]	萨蔷, 徐航程, 王佳玉. 乳腺癌免疫治疗研究进展[J]. 国际肿瘤学杂志, 2024, 51(4): 227-234.