2. Academic Validation
  3. A second-generation eIF4A RNA helicase inhibitor exploits translational reprogramming as a vulnerability in triple-negative breast cancer

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

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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