Poster Presentation 36th Lorne Cancer Conference 2024

Modulating mRNA translation machinery to prevent and treat chemotherapy-resistant triple-negative breast cancer (#220)

Heloisa Helena HH Milioli 1 2 3 , Erin H Heyer 1 2 , Cerys C McCool 1 2 , Beatriz B San Juan 1 2 , Vanina V Rodriguez 1 , David D Thomas 1 2 3 , Christine C Chaffer 1 2 3
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. University of New South Wales, Sydney, NSW, Australia
  3. St Vincent’s Clinical School Faculty of Medicine, Sydney, NSW, Australia

Triple-negative breast cancer (TNBC) poses a significant challenge for precision therapy due to the lack of targetable drivers and its inherent heterogeneity, enhanced by phenotypic plasticity. Notably, cancer cells that invoke plasticity develop stem-like properties to drive invasiveness and metastasis and evade therapy. In this paradigm, cancer cells dynamically change cell state and function (Hanahan, 2022; Chaffer et al, 2011; Chaffer et al, 2013), represented as dynamic movement around a cancer cell state landscape (Burkhardt et al, 2022). Cancer cells activate molecular programs to orchestrate bi-directional state changes between non-cancer stem cell (non-CSC; epithelial) and highly aggressive CSC (hybrid epithelial/mesenchymal) states. By blocking or leveraging plasticity programs, we aim to prevent cell state change and ultimately treat chemotherapy-resistant CSCs (San Juan et al, 2022). In our primary transcriptomic analysis, we identified the eukaryotic initiation factor 5A (eIF5A), an essential component of the mRNA translation machinery, playing a pivotal role in driving and maintaining the chemotherapy-resistant CSC state. Increased levels of eIF5A are observed in CSCs, and also correlate with poor prognosis in TNBC (TCGA and METABRIC datasets) and other cancer types. We then sought to evaluate the effects of eIF5A inhibition in TNBC preclinical models using the eIF5A inhibitor deoxyhypusine synthase inhibitor N1-guanyl-1,7-diaminoheptane (GC7). At a low concentration of GC7 (10 μM), we observed significant inhibition of CSC proliferation and enhanced cytotoxicity in vitro in TNBC cell lines, as evidenced by proliferation assays and fluorescence-activated cell sorting. GC7 also inhibited CSC tumourigenicity and migration capabilities, by tumoursphere formation and the wound healing assay, respectively. In vivo, combination therapy elicited tumour growth inhibition and significant improvement in overall survival in TNBC patient-derived xenograft models. Our findings provide compelling evidence for combining compounds that modulate eIF5A-dependent translatome with chemotherapies to disrupt cell state changes. This approach holds promising clinical potential for preventing and effectively treating aggressive TNBC, and possibly other aggressive malignancies.

 

 

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