微小突变在肿瘤耐药中的作用_修正版

1、修正版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（A? G）或嘧啶转换为嘧啶（C? T），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；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, Silva WM, Berger M, Bass C

2、, et al. Mutation(G275E) of the nicotinic；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5-7Furma n 等使用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。brut inib （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

3、长因子受体（epi dermal growthfactorrecep tor,EGFR)基因在 exon 21codo n843(p.V843l/c.2527G>A/COSMICID 85894)的微小突变检测，可以预测EGFRTKI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 anapiastic 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

4、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

5、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 partiallycon tributes to the D-cycloseri ne resista nee trait of Mycobacterium bovis BCGvaccine strains.PloS one 2012; 7(8): e43467.2. Che n L, Zhu S, Lu X, Pang 乙 Cai M, Liu X. Assess ing the risk that Phyt

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8、icolaides NC, Roberts ML, Kino T, et al. A novel point mutati on of the huma n glucocorticoid recep tor gene causes p rimary gen eralized glucocorticoid resista neethroughimp airedin teract ionwith the LXXLL motif of the p 160 coactivators:dissociationof the transactivatingand transreppressive activ

9、ities. The Journal of2014; 99 (5): E902-7.cli ni cal en docri no logy and metabolism6. Roberts ML, Ki no T, Nicolaides NC, et al. A no velpoi ntmutatio nin theDNA-bi nding domai n (DBD) of the huma n glucocorticoid recep tor causes p rimary gen eralized glucocorticoid resista nee by disr up ti ng th

10、e hydr op hobic structure of its2013; 98 (4): E790-5.DBD. The Jour nal of cli nical en docri no logy and metabolism7. Zhu HJ, DaiYF, Wang O, et al. Generalizedglucocorticoidresista neeacco mpaniedwithan adre nocortical ade noma andcaused by a novel pointmutation of humanglucocorticoidreceptor gene.

11、Chinese medical journal 2011;124 (4): 551-5.8. Furman RR, Che ng S, Lu P, et al. Ibrut inibresista nee in chronic lymp hocyticleukemia. The New En gla nd jour nal of medic ine2014; 370 (24): 2352-4.9. Demierre N, Zoete V, Michielin O, et al. Adramatic lung cancer course in apatie nt with a rare EGFR germl ine mutatio n exon 21 V843I: Is EGFR TKI resista neepredictable?Lung cancer 2013; 80 (1): 81-4.10. Awad MM, Katayama R, McTigue M, et al. Acquired resista nee to crizot inib froma mutationin CD74-ROS1. The New England journal of medicine 2013; 368 (25):2395-401.11. Sun H