微小突变在肿瘤耐药中的作用.docx

微小突变在肿瘤耐药中的作用微小突变是（micromutation）指基因中一个或几个核苷酸发生变化，既包括嘌呤转换为嘌呤的（AG）或嘧啶转换为嘧啶（CT），亦包括嘌呤与嘧啶的相互转换，引起编码蛋白质的一个或几个氨基酸的变化，进而引起细胞生物学性状及功能的变化。微小突变在不同的生命体中发挥着重要作用，cycA的微小突变使分枝杆菌具有抗D-环丝氨酸性特征1；真菌体内纤维素酶-3的微小突变可引起羧酸酰胺类杀真菌剂抗性2；昆虫体内谷氨酸门控氯离子通道或烟碱型乙酰胆碱受体及对位型钠通道的微小突变均可引起对杀虫药物的耐受3, 4；人体细胞内糖皮质激素受体DNA结构域的微小突变可产生原发性糖皮质激素耐受5-7。越来越多的研究发现，微小突变与肿瘤耐药性的产生密切相关，有可能成为预测肿瘤耐药的指标，进而可能成为可肿瘤耐药的靶点。Furman等使用brutinib（一种高效精确的靶向抗癌药物）治疗慢性淋巴细胞白血病时产生耐药，结构和生化实验证实在大约90%的复发后血病细胞中Bruton酪氨酸激酶（BTK）的微小突变致ibrutinib与突变BTK结合的可能性降低了500倍，使白血病细胞产生了耐药8。Demierre等研究发现表皮生长因子受体（epidermal growth factor receptor, EGFR)基因在 exon 21 codon 843 (p.V843I/c.2527GA/COSMIC ID 85894)的微小突变检测，可以预测EGFR TKI耐药性9。Awad等研究者在用Crizotinib（间变性淋巴瘤激酶的抑制剂an anaplastic lymphoma kinase，ALK）治疗肺癌的患者中发现，对crizotinib耐药伴有CD74-ROS1重排转移性肺腺癌患者开始的治疗效果显著，后很快产生耐药，活检肿瘤并测序发现ROS1激酶结构域存在获得性甘氨酸到精氨酸替代密码子2032微小突变，尽管这种突变并不在于在管家基因残基，但通过与药物结合从空间结构上干扰ROS1激酶抑制，结果显示微小突变可能是肿瘤耐药演化的早期事件10。Zirm等研究者在用Crizotinib 治疗伴有ALK 非活性位点C1156Y微小突变的非小细胞肺癌时，发现C1156Y通过结合腔的间接的构象变化使crizotinib的结合脱节，致rizotinib和ALK之间的静电相互作用和范德华力显著减少，结果提供了克服crizotinib耐药的重要线索11。因此原发和继发耐药的产生过程中微小突变均可能承担着重要角色，而有关微小突变在耐药方向的研究仍然处于起步阶段，随着测序技术的不断进步，深入研究耐药肿瘤的微小突变为克服肿瘤耐药提供了一条有效的途径。参考文献1.Chen JM, Uplekar S, Gordon SV, Cole ST. A point mutation in cycA partially contributes to the D-cycloserine resistance trait of Mycobacterium bovis BCG vaccine strains. PloS one 2012; 7(8): e43467.2.Chen L, Zhu S, Lu X, Pang Z, Cai M, Liu X. Assessing the risk that Phytophthora melonis can develop a point mutation (V1109L) in CesA3 conferring resistance to carboxylic acid amide fungicides. PloS one 2012; 7(7): e42069.3.Kwon DH, Yoon KS, Clark JM, Lee SH. A point mutation in a glutamate-gated chloride channel confers abamectin resistance in the two-spotted spider mite, Tetranychus urticae Koch. Insect molecular biology 2010; 19(4): 583-91.4.Puinean AM, Lansdell SJ, Collins T, Bielza P, Millar NS. A nicotinic acetylcholine receptor transmembrane point mutation (G275E) associated with resistance to spinosad in Frankliniella occidentalis. Journal of neurochemistry 2013; 124(5): 590-601.5.Nicolaides NC, Roberts ML, Kino T, et al. A novel point mutation of the human glucocorticoid receptor gene causes primary generalized glucocorticoid resistance through impaired interaction with the LXXLL motif of the p160 coactivators: dissociation of the transactivating and transreppressive activities. The Journal of clinical endocrinology and metabolism 2014; 99(5): E902-7.6.Roberts ML, Kino T, Nicolaides NC, et al. A novel point mutation in the DNA-binding domain (DBD) of the human glucocorticoid receptor causes primary generalized glucocorticoid resistance by disrupting the hydrophobic structure of its DBD. The Journal of clinical endocrinology and metabolism 2013; 98(4): E790-5.7.Zhu HJ, Dai YF, Wang O, et al. Generalized glucocorticoid resistance accompanied with an adrenocortical adenoma and caused by a novel point mutation of human glucocorticoid receptor gene. Chinese medical journal 2011; 124(4): 551-5.8.Furman RR, Cheng S, Lu P, et al. Ibrutinib resistance in chronic lymphocytic leukemia. The New England journal of medicine 2014; 370(24): 2352-4.9.Demierre N, Zoete V, Michielin O, et al. A dramatic lung cancer course in a patient with a rare EGFR germline mutation exon 21 V843I: Is EGFR TKI resistance predictable? Lung cancer 2013; 80(1): 81-4.10.Awad MM, Katayama R, McTigue M, et al. Acquired resistance to crizotinib from a mutation in CD74-ROS1. The New England journal of medicine 2013; 368(25): 2395-401.11.Sun HY