MicroRNA-16 Restores Sensitivity to Tyrosine Kinase Inhibitors and Outperforms MEK Inhibitors in KRAS-Mutated Non-Small Cell Lung Cancer.
MicroRNA-16 Restores Sensitivity to Tyrosine Kinase Inhibitors and Outperforms MEK Inhibitors in KRAS-Mutated Non-Small Cell Lung Cancer.
复制标题
DOI：
10.3390/ijms222413357
复制
发表时间：
2021-12-12
影响因子：
5.6
通讯作者：
Fabbri M
中科院分区：
文献类型：
--
作者：
Fanini F;Bandini E;Plousiou M;Carloni S;Wise P;Neviani P;Murtadha M;Foca F;Fabbri F;Vannini I;Fabbri M
背景：非小细胞肺癌(NSCLC)是全球癌症死亡的主要原因。化疗是不可手术病例的首选治疗方法，其成功率令人沮丧，这增加了对新治疗选择的需求。在大约25%的非小细胞肺癌中，KRAS癌基因的激活突变定义了一个亚类，该亚类无法受益于酪氨酸激酶抑制剂(TKI)。肿瘤抑制基因miR-16在包括非小细胞肺癌在内的许多人类癌症中表达下调。本研究的主要目的是评价miR-16治疗恢复TKI敏感性的效果，并比较其与MEK抑制剂在KRAS突变的NSCLC中的疗效。方法：我们进行了体外和体内研究，以探讨miR-16是否可以被用来克服KRAS突变的NSCLC对TKI的耐药性。我们有三个目标：第一，确定mir-16靶向的KRAS下游效应；第二，研究miR-16修复对KRAS突变的非小细胞肺癌TKI耐药的体内外影响；最后，比较miR-16和MEK抑制剂selumetinib在体内外抑制KRAS突变的NSCLC生长的作用。结果：我们证明miR-16在非小细胞肺癌中直接针对KRAS下游的三个效应分子MAPK3、MAP2K1和CRAF，在体内外恢复了KRAS突变的NSCLC对厄洛替尼的敏感性。我们还提供了证据表明，miR-16-erlotinib方案在治疗KRAS突变的非小细胞肺癌方面比selumetinib-erlotinib联合方案更有效。结论：我们的研究结果支持miR-16联合厄洛替尼治疗KRAS激活突变的非小细胞肺癌的临床前生物学基础。
Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. Chemotherapy, the treatment of choice in non-operable cases, achieves a dismal success rate, raising the need for new therapeutic options. In about 25% of NSCLC, the activating mutations of the KRAS oncogene define a subclass that cannot benefit from tyrosine kinase inhibitors (TKIs). The tumor suppressor miR-16 is downregulated in many human cancers, including NSCLC. The main objectives of this study were to evaluate miR-16 treatment to restore the TKI sensitivity and compare its efficacy to MEK inhibitors in KRAS-mutated NSCLC. Methods: We performed in vitro and in vivo studies to investigate whether miR-16 could be exploited to overcome TKI resistance in KRAS-mutated NSCLC. We had three goals: first, to identify the KRAS downstream effectors targeted by mir-16, second, to study the effects of miR-16 restoration on TKI resistance in KRAS-mutated NSCLC both in vitro and in vivo, and finally, to compare miR-16 and the MEK inhibitor selumetinib in reducing KRAS-mutated NSCLC growth in vitro and in vivo. Results: We demonstrated that miR-16 directly targets the three KRAS downstream effectors MAPK3, MAP2K1, and CRAF in NSCLC, restoring the sensitivity to erlotinib in KRAS-mutated NSCLC both in vitro and in vivo. We also provided evidence that the miR-16–erlotinib regimen is more effective than the selumetinib–erlotinib combination in KRAS-mutated NSCLC. Conclusions: Our findings support the biological preclinical rationale for using miR-16 in combination with erlotinib in the treatment of NSCLC with KRAS-activating mutations.
登录
查看更多内容
DOI：
10.1097/ppo.0b013e318250c001
发表时间：
2012-05
期刊：
Cancer journal (Sudbury, Mass.)
影响因子：
--
作者：
Iorio MV;Croce CM
通讯作者：
Croce CM
影响因子：
2.3
作者：
Jazieh AR;Al Sudairy R;Abu-Shraie N;Al Suwairi W;Ferwana M;Murad MH
通讯作者：
Murad MH
影响因子：
5.7
作者：
Davies, Barry R.;Logie, Armelle;Smith, Paul D.
通讯作者：
Smith, Paul D.
影响因子：
3.8
作者：
Krypuy M;Newnham GM;Thomas DM;Conron M;Dobrovic A
通讯作者：
Dobrovic A
miR-30a-5p过表达可以通过调节非小细胞肺癌细胞系中的PI3K/AKT信号通路来克服EGFR抑制剂的耐药性。
影响因子：
3.7
作者：
Meng F;Wang F;Wang L;Wong SC;Cho WC;Chan LW
通讯作者：
Chan LW