دورية أكاديمية

Efficacy of a Novel Bi-Steric mTORC1 Inhibitor in Models of B-Cell Acute Lymphoblastic Leukemia

التفاصيل البيبلوغرافية
العنوان: Efficacy of a Novel Bi-Steric mTORC1 Inhibitor in Models of B-Cell Acute Lymphoblastic Leukemia
المؤلفون: Bianca J. Lee, Sharmila Mallya, Nuntana Dinglasan, Amos Fung, Tram Nguyen, Lee-or Herzog, Joshua Thao, Edward G. Lorenzana, David Wildes, Mallika Singh, Jacqueline A. M. Smith, David A. Fruman
المصدر: Frontiers in Oncology, Vol 11 (2021)
بيانات النشر: Frontiers Media S.A., 2021.
سنة النشر: 2021
المجموعة: LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
مصطلحات موضوعية: mTORC1, targeted (selective) treatment, 4EBP1, combination therapy, Ph+ B-ALL, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
الوصف: The mechanistic target of rapamycin (mTOR) is a kinase whose activity is elevated in hematological malignancies. mTOR-complex-1 (mTORC1) phosphorylates numerous substrates to promote cell proliferation and survival. Eukaryotic initiation factor 4E (eIF4E)-binding proteins (4E-BPs) are mTORC1 substrates with an integral role in oncogenic protein translation. Current pharmacological approaches to inhibit mTORC1 activity and 4E-BP phosphorylation have drawbacks. Recently we described a series of bi-steric compounds that are potent and selective inhibitors of mTORC1, inhibiting 4E-BP phosphorylation at lower concentrations than mTOR kinase inhibitors (TOR-KIs). Here we report the activity of the mTORC1-selective bi-steric inhibitor, RMC-4627, in BCR-ABL-driven models of B-cell acute lymphoblastic leukemia (B-ALL). RMC-4627 exhibited potent and selective inhibition of 4E-BP1 phosphorylation in B-ALL cell lines without inhibiting mTOR-complex-2 (mTORC2) activity. RMC-4627 suppressed cell cycle progression, reduced survival, and enhanced dasatinib cytotoxicity. Compared to a TOR-KI compound, RMC-4627 was more potent, and its effects on cell viability were sustained after washout in vitro. Notably, a once-weekly, well tolerated dose reduced leukemic burden in a B-ALL xenograft model and enhanced the activity of dasatinib. These preclinical studies suggest that intermittent dosing of a bi-steric mTORC1-selective inhibitor has therapeutic potential as a component of leukemia regimens, and further study is warranted.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 2234-943X
Relation: https://www.frontiersin.org/articles/10.3389/fonc.2021.673213/full; https://doaj.org/toc/2234-943X
DOI: 10.3389/fonc.2021.673213
URL الوصول: https://doaj.org/article/0ce53ca3736040b0b923689cf9147f19
رقم الأكسشن: edsdoj.0ce53ca3736040b0b923689cf9147f19
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:2234943X
DOI:10.3389/fonc.2021.673213