Selective mTORC2 Inhibitor Therapeutically Blocks Breast Cancer Cell Growth and Survival.
Selective mTORC2 Inhibitor Therapeutically Blocks Breast Cancer Cell Growth and Survival.
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DOI：
10.1158/0008-5472.can-17-2388
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发表时间：
2018-04-01
期刊：
影响因子：
11.2
通讯作者：
Duvall CL
中科院分区：
文献类型：
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作者：
Werfel TA;Wang S;Jackson MA;Kavanaugh TE;Joly MM;Lee LH;Hicks DJ;Sanchez V;Ericsson PG;Kilchrist KV;Dimobi SC;Sarett SM;Brantley-Sieders DM;Cook RS;Duvall CL
mTORC 2激酶的小分子抑制剂（torkinibs）已在早期临床试验中显示出疗效。然而，研究中的torkinib也抑制其他含mTOR的复合物mTORC 1。虽然mTORC 1/mTORC 2组合抑制可能对癌细胞有益，但最近的报道描述了mTORC 1抑制后的补偿性细胞存活，这是由于PI 3 K负反馈的丧失、自噬增加和巨胞饮增加。遗传模型表明，选择性mTORC 2抑制剂在乳腺癌中是有效的，但迄今为止，缺乏mTORC 2的选择性小分子抑制剂已经排除了对这一假设的检验。在这里，我们报告了一种基于纳米颗粒的RNAi治疗剂的工程设计，该治疗剂可以有效地沉默mTORC 2专性辅因子Rictor。在肿瘤内和静脉内递送后，在HER 2扩增的乳腺肿瘤中实现了基于纳米颗粒的Rictor消融，降低了Akt磷酸化并增加了肿瘤细胞杀伤。体内选择性mTORC 2抑制剂与HER 2抑制剂拉帕替尼联合使用，比单独使用任何一种药物更大程度地降低了HER 2扩增乳腺癌的生长，表明mTORC 2促进拉帕替尼耐药，但被mTORC 2抑制剂克服。重要的是，选择性mTORC 2抑制在TNBC模型中有效，减少Akt磷酸化和肿瘤生长，这与我们的发现一致，即RICTOR mRNA与基底样TNBC患者的预后较差相关。总之，我们的研究结果提供了一种用于乳腺癌治疗基因消融的新型RNAi递送平台的临床前验证，并且它们表明mTORC 2选择性靶向在这种疾病环境中是可行和有效的。
Small molecule inhibitors of the mTORC2 kinase (torkinibs) have shown efficacy in early clinical trials. However, the torkinibs under study also inhibit the other mTOR-containing complex mTORC1. While mTORC1/mTORC2 combined inhibition may be beneficial in cancer cells, recent reports describe compensatory cell survival upon mTORC1 inhibition due to loss of negative feedback on PI3K, increased autophagy, and increased macropinocytosis. Genetic models suggest that selective mTORC2 inhibition would be effective in breast cancers, but the lack of selective small molecule inhibitors of mTORC2 have precluded testing of this hypothesis to date. Here we report the engineering of a nanoparticle-based RNAi therapeutic that can effectively silence the mTORC2 obligate cofactor Rictor. Nanoparticle-based Rictor ablation in HER2-amplified breast tumors was achieved following intra-tumoral and intra-venous delivery, decreasing Akt phosphorylation and increasing tumor cell killing. Selective mTORC2 inhibition in vivo, combined with the HER2 inhibitor lapatinib, decreased the growth of HER2-amplified breast cancers to a greater extent than either agent alone, suggesting that mTORC2 promotes lapatinib resistance but is overcome by mTORC2 inhibition. Importantly, selective mTORC2 inhibition was effective in a TNBC model, decreasing Akt phosphorylation and tumor growth, consistent with our findings that RICTOR mRNA correlates with worse outcome in patients with basal-like TNBC. Together, our results offer preclinical validation of a novel RNAi delivery platform for therapeutic gene ablation in breast cancer, and they show that mTORC2-selective targeting is feasible and efficacious in this disease setting.