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

  • Proc Natl Acad Sci U S A. 2024 Jan 23;121(4):e2318093121. doi: 10.1073/pnas.2318093121.
Regina Cencic  #  1  2 ,  Young K Im  #  3 ,  Sai Kiran Naineni  1  2 ,  Mohamed Moustafa-Kamal  1  2 ,  Predrag Jovanovic  3  4 ,  Valerie Sabourin  3 ,  Matthew G Annis  2 ,  Francis Robert  1  2 ,  T Martin Schmeing  1  2 ,  Antonis Koromilas  3  4  5 ,  Marilène Paquet  6 ,  Jose G Teodoro  1  2 ,  Sidong Huang  1  2 ,  Peter M Siegel  1  2  4  5  7 ,  Ivan Topisirovic  1  3  4  5 ,  Josie Ursini-Siegel  #  1  3  4  5 ,  Jerry Pelletier  #  1  2  4  5
Affiliations
  • 1. Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada.
  • 2. Rosalind & Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada.
  • 3. Lady Davis Institute for Medical Research, Montreal, QC H3T 1E2, Canada.
  • 4. Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada.
  • 5. Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H4A 3T2, Canada.
  • 6. Département de pathologie et de microbiologie, Faculté de médecine vétérinaire, Université de Montréal, Montréal, QC H3C 3J7, Canada.
  • 7. Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada.
  • # Contributed equally.
PMID: 38232291 DOI: 10.1073/pnas.2318093121
Abstract

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.

Keywords
eIF4A; lung metastasis; mRNA translation; triple-negative breast cancer.
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