The novel Mnk1/2 degrader and apoptosis inducer VNLG-152 potently inhibits TNBC tumor growth and metastasis
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AbstractCurrently, there are no effective therapies for patients with triple-negative breast cancer (TNBC), an aggressive and highly metastatic disease. Activation of eukaryotic initiation factor 4E (eIF4E) by mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (Mnk1/2) play a critical role in the development, progression and metastasis of TNBC. Herein, we undertook a comprehensive study to evaluate the activity of a first-in-class Mnk1/2 protein degraders, racemic VNLG-152R and its two enantiomers (VNLG-152E1 and VNLG-152E2) in in vitro and in vivo models of TNBC. These studies enabled us to identify racemic VNLG-152R as the most efficacious Mnk1/2 degrader, superior to its pure enantiomers. By targeting Mnk1/2 protein degradation (activity), VNLG-152R potently inhibited both Mnk-eIF4E and mTORC1 signaling pathways and strongly regulated downstream factors involved in cell cycle regulation, apoptosis, pro-inflammatory cytokines/chemokines secretion, epithelial-mesenchymal transition (EMT) and metastasis. Most importantly, orally bioavailable VNLG-152R exhibited remarkable antitumor (91 to 100% growth inhibition) and antimetastatic (~80% inhibition) activities against cell line and patient-derived TNBC xenograft models, with no apparent host toxicity. Collectively, these studies demonstrate that targeting Mnk-eIF4E/mTORC1 signaling with a potent Mnk1/2 degrader, VNLG-152R, is a novel therapeutic strategy that can be developed as monotherapy for the effective treatment of patients with primary/metastatic TNBC. Copyright 2019 by the authors. Licensee MDPI, Basel, Switzerland.
SponsorsThis work was supported in part by grants from the National Institutes of Health (NIH) and the National Cancer Institute (NCI) (R01CA129379, R21195694, and R01CA224696), start-up funds from University of Maryland School of Medicine and the Center for Biomolecular Therapeutics (CBT), Baltimore, USA and a Maryland Innovative Initiative (MII) Phase I grant from Maryland Technology Development Corporation (TEDCO) to VCON.
Mnk-eIF4E/mTORC1 signaling pathways
Triple negative breast cancer
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85063405244&doi=10.3390%2fcancers11030299&partnerID=40&md5=38831b658c28c91bda56edc9d54abee4; http://hdl.handle.net/10713/10792