Abstract B30: Inhibition of eIF4E/MNK axis by novel MNKDAs reduces breast cancer tumor growth, migration, invasion and metastasis

Abstract Triple-negative breast cancer (TNBC) represents a molecularly heterogeneous subgrouping of high-risk breast tumors characterized by aggressive behavior, poor prognosis and lack of targeted therapeutic options. The translation initiation factor eIF4E, an oncogene essential for cap-dependent translation of specific mRNAs critical for cell division, cell survival, angiogenesis, and metastasis is commonly overexpressed in primary breast cancers including TNBC. eIF4E therapeutic targeting is considered novel and significant because tumor cells specifically overexpress eIF4E and develop an oncogene addiction to eIF4E, rendering the cells vulnerable to eIF4E inhibition, whereas normal cells are relatively insensitive. Phosphorylation of eIF4E at serine-209 is critical for the oncogenic activity of eIF4E, and it has been suggested that chemical compounds that prevent the phosphorylation of eIF4E could act as effective anticancer drugs. Herein, we report that a novel inhibitor of peIF4E function (Novel Retinamides, NRs), safely and potently suppresses breast tumor formation. Administration of novel retinamides (mnk degrading agents: MNKDAs) blocked the growth of primary breast tumors in MDA-MB-231 xenograft model, TNBC patient derived xenografts (PDX), and reduced the development of lung metastases in an invasive model. Mechanistically, NRs resulted in the degradation of MNKs (MNK1 and MNK2), a key kinase chiefly responsible for phosphorylating and activating eIF4E. This in turn hampered peIF4E involved translation initiation and activation of genes associated with cell proliferation and survival. Furthermore, MNK degradation by NRs also suppressed epithelial-to-mesenchymal transition, a process crucial for metastasis as evident by increased expression of E-cadherin and reduced expression of N-cadherin, fibronectin and vimentin; snail, slug, twist, fibronectin, claudin, lamin, TCF/ZEB-1, beta catenin, MMPs and vimentin. Taken together, the preclinical evidence of tumor regression and metastasis in TNBC models suggest that NRs offers considerable promise as new therapeutic candidate to target TNBC and metastatic breast cancer. Citation Format: Senthilmurugan Ramalingam, Lalji Gediya, Vidya Ramamurthy, Yong Choi, Rena Lapidus, Njar Vincent. Inhibition of eIF4E/MNK axis by novel MNKDAs reduces breast cancer tumor growth, migration, invasion and metastasis. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B30.