Abstract 756: First MNK degrading agents block phosphorylation of eIF4E, induce apoptosis, and inhibit cell growth, migration and invasion in triple-negative and HER2-overexpressing breast cancer cell lines

Abstract

Abstract Introduction: Retinoic acid metabolism blocking agents are known to exhibit a range of anticarcinogenic properties. This study investigated the anticancer efficacy of novel, potent retinamide retinoic acid metabolism blocking agents (RRs) in triple negative and Her 2 overexpressing breast cancer cells. Recent findings suggest that overexpression of eukaryotic translation initiation factor 4E (eIF4E) in breast cancers critically augments CAP-dependent mRNA translation and synthesis of proteins involved in cell growth, cell proliferation, invasion and apoptosis evasion. The oncogenic potential of eIF4E is strictly dependent on serine 209 phosphorylation by upstream MAPK-interacting kinases (Mnk). Targeting Mnk/eIF4E pathway for blocking Mnk function and eIF4E phosphorylation is therefore a novel approach for treating breast cancers particularly for HER-2-positive and triple negative breast cancers that have no indications for endocrine therapy or effective treatment regimes. Methods: Triple negative and Her 2 overexprssing breast cancer cells were treated with retinamide RAMBAs and Mnk inhibitors and evaluated the effects of RRs on growth inhibition, MAPK/Mnk mediated eIF4E protein translational machinery and downstream biological effects in triple negative and Her 2 overexpressing breast cancer cells Results: We report that the degradation of Mnk by RRs in breast cancer cells blocks eIF4E phosphorylation and subsequently inhibits cell growth, invasion and metastasis in addition to inducing apoptosis. Most importantly the anticancer efficacy of RRs was mediated via degrading Mnk rather than inhibiting its kinase activity like Mnk inhibitors (Cercosporamide and CGP 57380). RRs effect on p-eIF4E downregulation and growth inhibition were also far more potent than the clinically relevant retinoids and Mnk inhibitors, cercosporamide and CGP 57380. Conclusion: Together our findings provide the first preclinical proof-of-concept of novel Mnk degrading agents for Mnk based therapeutic treatment of breast cancers. Citation Format: Senthilmurugan Ramalingam, Lalji Gediya, Puranik Purushottamachar, Andrew Kwegyir-Afful, Vidya priyadarsini Ramamurthy, Hannah Mbatia, Vincent Njar. First MNK degrading agents block phosphorylation of eIF4E, induce apoptosis, and inhibit cell growth, migration and invasion in triple-negative and HER2-overexpressing breast cancer cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 756. doi:10.1158/1538-7445.AM2014-756