转移性结直肠癌西妥昔单抗耐药的分子机制

doi:10.3760/cma.j.cn371439-20200208-00025

国际肿瘤学杂志 ›› 2020, Vol. 47 ›› Issue (5): 308-311.doi: 10.3760/cma.j.cn371439-20200208-00025

转移性结直肠癌西妥昔单抗耐药的分子机制

苏昊¹, 刘文杰²(), 包满都拉¹, 罗寿¹, 王雪玮¹, 赵传多¹, 刘骞¹, 王锡山¹, 周志祥¹, 周海涛¹()

¹ 国家癌症中心/国家肿瘤临床医学研究中心/中国医学科学院北京协和医学院肿瘤医院结直肠外科 100021
² 国家癌症中心/国家肿瘤临床医学研究中心/中国医学科学院北京协和医学院肿瘤医院肝胆外科实验室 100021

收稿日期:2020-02-08 修回日期:2020-03-01 出版日期:2020-05-08 发布日期:2020-07-02
通讯作者: 刘文杰 E-mail:wenjie6363@163.com;zhouhaitao01745@163.com
基金资助:
中国医学科学院医学与健康科技创新工程(2017-I2M-4-002);北京协和医学院2018年度研究生创新基金(2018-1002-02-26)

Molecular mechanisms of cetuximab resistance in metastatic colorectal cancer

Su Hao¹, Liu Wenjie²(), Bao Mandula¹, Luo Shou¹, Wang Xuewei¹, Zhao Chuanduo¹, Liu Qian¹, Wang Xishan¹, Zhou Zhixiang¹, Zhou Haitao¹()

¹ Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100021, China
² Laboratory of Hepatological Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100021, China

Received:2020-02-08 Revised:2020-03-01 Online:2020-05-08 Published:2020-07-02
Contact: Liu Wenjie E-mail:wenjie6363@163.com;zhouhaitao01745@163.com
Supported by:
Chinese Academy of Medical Sciences Initiative for Innovative Medicine(2017-I2M-4-002);Postgraduate Innovation Fund Project of Peking Union Medical College in 2018(2018-1002-02-26)

摘要/Abstract

摘要：

西妥昔单抗是治疗转移性结直肠癌(mCRC)重要的分子靶向药物,可增加化疗疗效并延长患者生存期,但是部分患者对该类药物存在不敏感或耐药现象,其分子机制尚未完全揭示。随着表皮生长因子受体(EGFR)信号通路研究的深入,KRAS、BRAF、PTEN、PIK3CA等基因的改变以及微小RNA(miRNA)的多态性逐渐被证实与西妥昔单抗耐药相关,最新的研究亦表明Wnt信号通路及其负性调控因子RNF43可能与西妥昔单抗耐药相关。总结mCRC西妥昔单抗耐药分子机制的研究进展,可为后续寻找治疗药物奠定理论基础。

关键词: 结直肠肿瘤, 分子靶向治疗, 分子生物学, 抗药性, 分子机制

Abstract:

Cetuximab has become an important molecular targeted drug for the treatment of metastatic colorectal cancer (mCRC), which increases the curative effect of chemotherapy and prolongs the survival time. However, some patients develop insensitiveness or resistance to cetuximab, while the complicated molecular mechanisms are not quite clear. With the deep research in epidermal growth factor receptor (EGFR) signaling pathway, the genetic alteration of KRAS, BRAF, PTEN and PIK3CA and polymorphism of microRNA (miRNA) have been proved to associated with cetuximab resistance. Wnt signaling pathway with its negative regulator RNF43 is also considered to be related with cetuximab resistance in recent studies. The review of the progress on molecular mechanisms of cetuximab resistance in mCRC can establish theoretical basis for finding out reasonable drugs to overcome the resistance.

Key words: Colorectal neoplasms, Molecular targeted therapy, Molecular biology, Drug resistance, Molecular mechanism

苏昊, 刘文杰, 包满都拉, 罗寿, 王雪玮, 赵传多, 刘骞, 王锡山, 周志祥, 周海涛. 转移性结直肠癌西妥昔单抗耐药的分子机制[J]. 国际肿瘤学杂志, 2020, 47(5): 308-311.

Su Hao, Liu Wenjie, Bao Mandula, Luo Shou, Wang Xuewei, Zhao Chuanduo, Liu Qian, Wang Xishan, Zhou Zhixiang, Zhou Haitao. Molecular mechanisms of cetuximab resistance in metastatic colorectal cancer[J]. Journal of International Oncology, 2020, 47(5): 308-311.

参考文献 30

[1]	Kirstein MM, Lange A, Prenzler A, et al. Targeted therapies in metastatic colorectal cancer: a systematic review and assessment of currently available data[J]. Oncologist, 2014,19(11):1156-1168. DOI: 10.1634/theoncologist.2014-0032. doi: 10.1634/theoncologist.2014-0032
[2]	李敏敏, 毕祥, 王哲海. 转移性结直肠癌抗EGFR单抗获得性耐药的研究进展[J]. 国际肿瘤学杂志, 2014,41(5):357-360. DOI: 10.3760/cma.j.issn.1673-422X.2014.05.012. doi: 10.3760/cma.j.issn.1673-422X.2014.05.012
[3]	Sotelo MJ, García-Paredes B, Aguado C, et al. Role of cetuximab in first-line treatment of metastatic colorectal cancer[J]. World J Gastroenterol, 2014,20(15):4208-4219. DOI: 10.3748/wjg.v20.i15.4208. doi: 10.3748/wjg.v20.i15.4208 pmid: 24764659
[4]	刘晓娜, 田庄, 魏晓飞, 等. 联合检测结直肠癌患者血浆及组织中KRAS、NRAS、BRAF及PIK3CA基因突变情况[J]. 中华病理学杂志, 2019,48(5):373-377. DOI: 10.3760/cma.j.issn.0529-5807.2019.05.008.
[5]	Limbach C, Laue MM, Wang X, et al. Molecular in situ topology of Aczonin/Piccolo and associated proteins at the mammalian neurotransmitter release site[J]. Proc Natl Acad Sci U S A, 2011,108(31):E392-E401. DOI: 10.1073/pnas.1101707108. doi: 10.1073/pnas.1101707108 pmid: 21712437
[6]	Douillard JY, Siena S, Cassidy J, et al. Randomized, phase Ⅲ trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study[J]. J Clin Oncol, 2010,28(31):4697-4705. DOI: 10.1200/JCO.2009.27.4860. doi: 10.1200/JCO.2009.27.4860 pmid: 20921465
[7]	Dienstmann R, De Dosso S, Felip E, et al. Drug development to overcome resistance to EGFR inhibitors in lung and colorectal cancer[J]. Mol Oncol, 2012,6(1):15-26. DOI: 10.1016/j.molonc.2011.11.009. doi: 10.1016/j.molonc.2011.11.009
[8]	Clark JI, Singh J, Ernstoff MS, et al. A multi-center phase Ⅱ study of high dose interleukin-2 sequenced with vemurafenib in patients with BRAF-V600 mutation positive metastatic melanoma[J]. J Immuno-ther Cancer, 2018,6(1):76. DOI: 10.1186/s40425-018-0387-x.
[9]	Van Cutsem E, Kohne CH, Láng I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colo-rectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status[J]. J Clin Oncol, 2011,29(15):2011-2019. DOI: 10.1200/JCO.2010.33.5091. doi: 10.1200/JCO.2010.33.5091
[10]	Hutchins G, Southward K, Handley K, et al. Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer[J]. J Clin Oncol, 2011,29(10):1261-1270. DOI: 10.1200/JCO.2010.30.1366. doi: 10.1200/JCO.2010.30.1366
[11]	Yuan ZX, Wang XY, Qin QY, et al. The prognostic role of BRAF mutation in metastatic colorectal cancer receiving anti-EGFR monoclonal antibodies: a meta-analysis[J]. PLoS One, 2013,8(6):e65995. DOI: 10.1371/journal.pone.0065995. doi: 10.1371/journal.pone.0065995 pmid: 23776587
[12]	Haddadi N, Lin Y, Travis G, et al. PTEN/PTENP1: 'regulating the regulator of RTK-dependent PI3K/Akt signalling', new targets for cancer therapy[J]. Mol Cancer, 2018,17(1):37. DOI: 10.1186/s12943-018-0803-3. doi: 10.1186/s12943-018-0803-3 pmid: 29455665
[13]	Frattini M, Saletti P, Romagnani E, et al. PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients[J]. Br J Cancer, 2007,97(8):1139-1145. DOI: 10.1038/sj.bjc.6604009. doi: 10.1038/sj.bjc.6604009 pmid: 17940504
[14]	Razis E, Pentheroudakis G, Rigakos G, et al. EGFR gene gain and PTEN protein expression are favorable prognostic factors in patients with KRAS wild-type metastatic colorectal cancer treated with cetu-ximab[J]. J Cancer Res Clin Oncol, 2014,140(5):737-748. DOI: 10.1007/s00432-014-1626-2. doi: 10.1007/s00432-014-1626-2 pmid: 24595598
[15]	De Roock W, Claes B, Bernasconi D, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis[J]. Lancet Oncol, 2010,11(8):753-762. DOI: 10.1016/S1470-2045(10)70130-3. doi: 10.1016/S1470-2045(10)70147-9 pmid: 20619739
[16]	Ueda T, Volinia S, Okumura H, et al. Relation between microRNA expression and progression and prognosis of gastric cancer: a micro-RNA expression analysis[J]. Lancet Oncol, 2010,11(2):136-146. DOI: 10.1016/S1470-2045(09)70343-2. doi: 10.1016/S1470-2045(09)70386-9 pmid: 20022810
[17]	Ruzzo A, Graziano F, Vincenzi B, et al. High let-7a microRNA levels in KRAS-mutated colorectal carcinomas may rescue anti-EGFR therapy effects in patients with chemotherapy-refractory metastatic disease[J]. Oncologist, 2012,17(6):823-829. DOI: 10.1634/theoncologist.2012-0081. doi: 10.1634/theoncologist.2012-0081
[18]	Mosakhani N, Lahti L, Borze I, et al. MicroRNA profiling predicts survival in anti-EGFR treated chemorefractory metastatic colorectal cancer patients with wild-type KRAS and BRAF[J]. Cancer Genet, 2012,205(11):545-551. DOI: 10.1016/j.cancergen.2012.08.003. doi: 10.1016/j.cancergen.2012.08.003 pmid: 23098991
[19]	Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer[J]. Oncogene, 2017,36(11):1461-1473. DOI: 10.1038/onc.2016.304. doi: 10.1038/onc.2016.304 pmid: 27617575
[20]	Ma Y, Yang Y, Wang F, et al. Long non-coding RNA CCAL regulates colorectal cancer progression by activating Wnt/β-catenin signalling pathway via suppression of activator protein 2α[J]. Gut, 2016,65(9):1494-1504. DOI: 10.1136/gutjnl-2014-308392. doi: 10.1136/gutjnl-2014-308392 pmid: 25994219
[21]	Hu T, Li C. Convergence between Wnt-β-catenin and EGFR signaling in cancer[J]. Mol Cancer, 2010,9(1):236. DOI: 10.1186/1476-4598-9-236. doi: 10.1186/1476-4598-9-236
[22]	Therkildsen C, Bergmann TK, Henrichsen-Schnack T, et al. The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: a systematic review and meta-analysis[J]. Acta Oncol, 2014,53(7):852-864. DOI: 10.3109/0284186X. doi: 10.3109/0284186X.2014.895036
[23]	Koo BK, Spit M, Jordens I, et al. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors[J]. Nature, 2012,488(7413):665-669. DOI: 10.1038/nature11308. doi: 10.1038/nature11308
[24]	徐星宇, 来茂德. 环指蛋白43的结构、功能及其在肿瘤中的作用[J]. 临床与实验病理学杂志, 2016,32(6):673-677. DOI: 10.13315/j.cnki.cjcep.2016.06.017.
[25]	Serra S, Chetty R. Rnf43[J]. J Clin Pathol, 2018,71(1):1-6. DOI: 10.1136/jclinpath-2017-204763. doi: 10.1136/jclinpath-2017-204763 pmid: 29018044
[26]	Lebensohn AM, Rohatgi R. R-spondins can potentiate WNT signaling without LGRs[J]. Elife, 2018,7:e33126. DOI: 10.7554/eLife.33126. doi: 10.7554/eLife.33126 pmid: 29405118
[27]	Yaeger R, Chatila WK, Lipsyc MD, et al. Clinical sequencing defines the genomic landscape of metastatic colorectal cancer[J]. Cancer Cell, 2018,33(1): 125-136.e3. DOI: 10.1016/j.ccell.2017.12.004. doi: 10.1016/j.ccell.2017.12.004 pmid: 29316426
[28]	Steinhart Z, Pavlovic Z, Chandrashekhar M, et al. Corrigendum: Genome-wide CRISPR screens reveal a Wnt-FZD5 signaling circuit as a druggable vulnerability of RNF43-mutant pancreatic tumors[J]. Nat Med, 2017,23(11):1384. DOI: 10.1038/nm1117-1384d. doi: 10.1038/nm1117-1384d pmid: 29117169
[29]	Coffey RJ, Hawkey CJ, Damstrup L, et al. Epidermal growth factor receptor activation induces nuclear targeting of cyclooxygenase-2, basolateral release of prostaglandins, and mitogenesis in polarizing colon cancer cells[J]. Proc Natl Acad Sci U S A, 1997,94(2):657-662. DOI: 10.1073/pnas.94.2.657. doi: 10.1073/pnas.94.2.657 pmid: 9012840
[30]	Lu Y, Zhao X, Liu Q, et al. lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/β-catenin signaling[J]. Nat Med, 2017,23(11):1331. DOI: 10.1038/nm.4424. doi: 10.1038/nm.4424 pmid: 29035371

转移性结直肠癌西妥昔单抗耐药的分子机制

Molecular mechanisms of cetuximab resistance in metastatic colorectal cancer

RichHTML

PDF

可视化

摘要/Abstract

引用本文

使用本文

参考文献 30

相关文章 15

编辑推荐

Metrics

本文评价

[1]	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.
[2]	张蕊, 褚衍六. 基于FIT与肠道菌群的结直肠癌风险评估模型的研究进展[J]. 国际肿瘤学杂志, 2024, 51(6): 370-375.
[3]	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.
[4]	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.
[5]	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.
[6]	杨智, 陆以乔, 顾花艳, 丁佳玲, 郭贵龙. 肿瘤微环境介导乳腺癌靶向治疗耐药的研究进展[J]. 国际肿瘤学杂志, 2024, 51(4): 235-238.
[7]	张栋岩, 王品, 魏秋亚, 邓成伍, 魏相相, 高远飞, 王琛. 索凡替尼靶向联合卡培他滨和奥沙利铂治疗肝内胆管癌术后患者1例及文献复习[J]. 国际肿瘤学杂志, 2024, 51(4): 249-253.
[8]	龚艳, 陈洪雷. 微RNA调控卵巢癌顺铂耐药的机制研究进展[J]. 国际肿瘤学杂志, 2024, 51(3): 186-190.
[9]	孙国宝, 杨倩, 庄庆春, 高斌斌, 孙晓刚, 宋伟, 沙丹. 结直肠癌肝转移组织病理学生长方式研究进展[J]. 国际肿瘤学杂志, 2024, 51(2): 114-118.
[10]	马正红, 姜超. 非小细胞肺癌KRAS^G12C突变的研究进展[J]. 国际肿瘤学杂志, 2024, 51(2): 95-98.
[11]	黄辉, 丁江华. 靶向FGFR2治疗晚期胆管癌的研究进展[J]. 国际肿瘤学杂志, 2023, 50(9): 569-573.
[12]	刘德宝, 孙子雯, 鲁守堂, 徐海东. ASB6在结直肠癌组织中的表达及临床意义[J]. 国际肿瘤学杂志, 2023, 50(8): 470-474.
[13]	安荣, 刘美华, 王佩晨, 王晓慧. Nrf2在卵巢癌中的研究进展[J]. 国际肿瘤学杂志, 2023, 50(8): 493-497.
[14]	李开春, 丁昌利, 于文艳. 安罗替尼联合特瑞普利单抗治疗晚期肺肉瘤样癌1例[J]. 国际肿瘤学杂志, 2023, 50(8): 511-512.
[15]	陈秋, 王雷, 王明琦, 张梅. 恩沃利单抗联合阿昔替尼治疗肾癌肺转移1例并文献复习[J]. 国际肿瘤学杂志, 2023, 50(7): 445-448.