Selective mTORC2 Inhibitor Therapeutically Blocks Breast Cancer Cell Growth and Survival
| Autor: | Paula Gonzalez Ericsson, Meghan Morrison Joly, Rebecca S. Cook, Violeta Sanchez, Samantha M. Sarett, Linus Lee, Meredith A. Jackson, Kameron V. Kilchrist, Shan Wang, Taylor E. Kavanaugh, Donna J. Hicks, Thomas A. Werfel, Dana M. Brantley-Sieders, Craig L. Duvall, Somtochukwu C. Dimobi |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Cell Survival Receptor ErbB-2 Mice Nude Antineoplastic Agents Triple Negative Breast Neoplasms Mechanistic Target of Rapamycin Complex 2 mTORC1 Lapatinib mTORC2 Article Mice 03 medical and health sciences Breast cancer Genetic model medicine Animals Humans RNA Small Interfering skin and connective tissue diseases Protein Kinase Inhibitors PI3K/AKT/mTOR pathway Cell Proliferation Mice Inbred BALB C Kinase business.industry medicine.disease Xenograft Model Antitumor Assays Disease Models Animal Rapamycin-Insensitive Companion of mTOR Protein 030104 developmental biology Oncology Cancer cell Cancer research Nanoparticles Female business medicine.drug |
| Zdroj: | Cancer Research. 78:1845-1858 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-17-2388 |
| Popis: | 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 intratumoral and intravenous 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 triple-negative breast cancer (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. Significance: This study describes a nanomedicine to effectively inhibit the growth regulatory kinase mTORC2 in a preclinical model of breast cancer, targeting an important pathogenic enzyme in that setting that has been undruggable to date. Cancer Res; 78(7); 1845–58. ©2018 AACR. |
| Databáze: | OpenAIRE |
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