Abstract
Currently, 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.
Highlights
Breast cancer (BC) is the most frequently diagnosed cancer among women in the United States and is the second leading cause of cancer-related death in women [1]
We have previously established that racemic VNLG-152R (Figure 1A) induces Mnk1/2 degradation to inhibit the growth of BC/triple-negative breast cancer (TNBC) cells by reducing proliferation and inducing apoptosis
VNLG-152R (5 μM) treatment of MDA-MB-231 cells harboring Mnk1 knockdown did not show any significant decrease in cell viability (Figure 1G, right panel), These results strongly suggest that Mnk1 is indispensable for VNLG-152R to mediate its growth inhibitory effects in MDA-MB-231 cells, and that loss of a prime target abolishes the growth-inhibitory effects mediated by VNLG-152R
Summary
Breast cancer (BC) is the most frequently diagnosed cancer among women in the United States and is the second leading cause of cancer-related death in women [1]. Eukaryotic initiation factor 4E (eIF4E), a component of “eIF4F cap binding complex” has crucial roles in mRNA discrimination and in driving the development and progression of various cancers including that of the breast [6,7]. EIF4G-associated eIF4E binds to m7G cap at the 50 -end of eukaryotic mRNAs, initiating translation of “weak mRNAs” encoding malignancy-related proteins [8,9]. Wheater et al [14] demonstrated that treatment of human breast cancer cells with Mnk inhibitors reduced colony formation, proliferation, and survival. Recent reports highlight the impact of inhibiting Mnk-eIF4E signaling in experiment and clinical settings of TNBC [21,22,23]
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