A second-generation eIF4A RNA helicase inhibitor exploits translational reprogramming as a vulnerability in triple-negative breast cancer

• Published in: Proceedings of the National Academy of Sciences - PNAS 2024-01, Vol.121 (4), p.e2318093121
• Main Authors: Cencic, Regina, Im, Young K, Naineni, Sai Kiran, Moustafa-Kamal, Mohamed, Jovanovic, Predrag, Sabourin, Valerie, Annis, Matthew G, Robert, Francis, Schmeing, T Martin, Koromilas, Antonis, Paquet, Marilène, Teodoro, Jose G, Huang, Sidong, Siegel, Peter M, Topisirovic, Ivan, Ursini-Siegel, Josie, Pelletier, Jerry
• Format: Article
• Language: English
• Subjects: Animals; Bioavailability; Biological Sciences; Breast cancer; Clinical trials; DNA helicase; Eukaryotic Initiation Factor-4A - genetics; Eukaryotic Initiation Factor-4A - metabolism; Heterogeneity; Humans; Metastases; Metastasis; Mice; mRNA; Protein Biosynthesis; Ribosomes - metabolism; RNA helicase; RNA Helicases - genetics; RNA Helicases - metabolism; Toxicity; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2318093121

In this study, we aimed to address the current limitations of therapies for macro-metastatic triple-negative breast cancer (TNBC) and provide a therapeutic lead that overcomes the high degree of heterogeneity associated with this disease. Specifically, we focused on well-documented but clinically underexploited cancer-fueling perturbations in mRNA translation as a potential therapeutic vulnerability. We therefore developed an orally bioavailable rocaglate-based molecule, MG-002, which hinders ribosome recruitment and scanning via unscheduled and non-productive RNA clamping by the eukaryotic translation initiation factor (eIF) 4A RNA helicase. We demonstrate that MG-002 potently inhibits mRNA translation and primary TNBC tumor growth without causing overt toxicity in mice. Importantly, given that metastatic spread is a major cause of mortality in TNBC, we show that MG-002 attenuates metastasis in pre-clinical models. We report on MG-002, a rocaglate that shows superior properties relative to existing eIF4A inhibitors in pre-clinical models. Our study also paves the way for future clinical trials exploring the potential of MG-002 in TNBC and other oncological indications.