Drug resistance profiles of mutations in the RET kinase domain
Drug resistance profiles of mutations in the RET kinase domain
复制标题
DOI：
10.1111/bph.14395
复制
发表时间：
2018-09-01
影响因子：
7.3
通讯作者：
Wu, Jie
中科院分区：
文献类型：
--
作者：
Liu, Xuan;Shen, Tao;Wu, Jie
背景和技术在甲状腺癌和肺癌中发现酪氨酸激酶RET的改变。尽管RET TK抑制剂（TKI）被用于治疗甲状腺癌，并且在RET融合阳性非小细胞肺癌的临床试验中，但RET激酶结构域中的突变对药物敏感性的影响在很大程度上是未表征的。凡德他尼和尼达尼布使用RET激酶依赖性BaF 3/KIF 5 B-RET（BaF 3/KR）细胞。我们还检测了RET（M918 T）（一种在侵袭性多发性内分泌腺瘤2B型中普遍存在的RET突变）对BaF 3/KR细胞中这些TKI的敏感性。在6个RET激酶结构域突变（L730 I、V738 A、V804 L/M、Y806 N、G810 S）中发现了对4种TKI的泛耐药。7个RET激酶结构域突变（L730 V、E732 K、A807 V、G810 A、V871 I、M918 T、F998 V）显示出对这些药物中的一种或多种的选择性耐药。L730 I/V和G810 A/S的耐药谱不同。V871 I，M918 T和F998 V突变位于远离TKI结合pocket.CONCLUSIONS和IMPLICATIONSA面板TKI耐药RET突变被确定，他们的药物敏感性交叉分析。本研究结果为选择合适的TKI抑制RET激酶结构域突变体提供了参考。除了药物相互作用残基的变化外，远端位点的突变可能产生长期影响，导致TKI耐药性。在此处分析的4种TKI中，尼达尼布未受3个远端位点突变的影响。
BACKGROUND AND PURPOSEAlterations in the tyrosine kinase enzyme RET are found in thyroid and lung cancer. While RET TK inhibitors (TKIs) are used to treat thyroid cancer and are in clinical trials for RET fusion-positive non-small cell lung cancer, the impact of mutations in the RET kinase domain on drug sensitivity is largely uncharacterized.EXPERIMENTAL APPROACHWe identified and analysed mutations in the RET kinase domain that conferred resistance to the TKIs cabozantinib, lenvatinib, vandetanib and nintedanib using RET kinase-dependent BaF3/KIF5B-RET (BaF3/KR) cells. We also examined the sensitivity of RET (M918T), a RET mutation prevalent in aggressive multiple endocrine neoplasia type 2B, to these TKIs in the context of BaF3/KR cells.KEY RESULTSFourteen mutations were analysed. Pan resistance to the four TKIs was found in six RET kinase domain mutations (L730I, V738A, V804L/M, Y806N, G810S). Seven RET kinase domain mutations (L730V, E732K, A807V, G810A, V871I, M918T, F998V) displayed selective resistance to one or more of these drugs. L730I/V and G810A/S had different drug resistance profiles. V871I, M918T and F998V mutations are located at distant sites away from the TKI binding pocket.CONCLUSIONS AND IMPLICATIONSA panel of TKI-resistant RET mutations were identified, and their drug sensitivities were cross-profiled. The results provide a reference for selecting appropriate TKIs to inhibit RET kinase domain mutants. Besides changes in the drug-interacting residues, mutations at distant sites could exert long-range effects resulting in TKI resistance. Among the four TKIs analysed here, nintedanib remained unaffected by mutations at the three distant sites.