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Selective mTORC2 Inhibitor Therapeutically Blocks Breast Cancer Cell Growth and Survival.
Werfel, Thomas A; Wang, Shan; Jackson, Meredith A; Kavanaugh, Taylor E; Joly, Meghan Morrison; Lee, Linus H; Hicks, Donna J; Sanchez, Violeta; Ericsson, Paula Gonzalez; Kilchrist, Kameron V; Dimobi, Somtochukwu C; Sarett, Samantha M; Brantley-Sieders, Dana M; Cook, Rebecca S; Duvall, Craig L.
Afiliação
  • Werfel TA; Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee.
  • Wang S; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
  • Jackson MA; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
  • Kavanaugh TE; Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee.
  • Joly MM; Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee.
  • Lee LH; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
  • Hicks DJ; Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee.
  • Sanchez V; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.
  • Ericsson PG; Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
  • Kilchrist KV; Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
  • Dimobi SC; Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee.
  • Sarett SM; Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee.
  • Brantley-Sieders DM; Department of Biomedical Engineering, Vanderbilt University, Nashville, Tennessee.
  • Cook RS; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
  • Duvall CL; Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.
Cancer Res ; 78(7): 1845-1858, 2018 04 01.
Article em En | MEDLINE | ID: mdl-29358172
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptor ErbB-2 / Ensaios Antitumorais Modelo de Xenoenxerto / RNA Interferente Pequeno / Inibidores de Proteínas Quinases / Proliferação de Células / Neoplasias de Mama Triplo Negativas / Alvo Mecanístico do Complexo 2 de Rapamicina / Lapatinib / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Cancer Res Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptor ErbB-2 / Ensaios Antitumorais Modelo de Xenoenxerto / RNA Interferente Pequeno / Inibidores de Proteínas Quinases / Proliferação de Células / Neoplasias de Mama Triplo Negativas / Alvo Mecanístico do Complexo 2 de Rapamicina / Lapatinib / Antineoplásicos Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Cancer Res Ano de publicação: 2018 Tipo de documento: Article