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

2024; National Academy of Sciences; Volume: 121; Issue: 4 Linguagem: Inglês

10.1073/pnas.2318093121

1091-6490

Regina Cencic, Young Kyuen Im, Sai Kiran Naineni, Mohamed Moustafa-Kamal, Predrag Jovanovic, Valérie Sabourin, Matthew G. Annis, Françis Robert, T.M. Schmeing, Antonis E. Koromilas, Marilène Paquet, Jose G. Teodoro, Sidong Huang, Peter M. Siegel, Ivan Topisirović, Josie Ursini‐Siegel, Jerry Pelletier,

RNA modifications and cancer

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.