Bcl-xl blockage in tnbc models confers vulnerability to inhibition of specific cell cycle regulators

Olivier Castellanet, Fahmida Ahmad, Yaron Vinik, Gordon B. Mills, Bianca Habermann, Jean Paul Borg, Sima Lev, Fabienne Lamballe, Flavio Maina

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Cell cycle regulators are frequently altered in Triple-Negative Breast Cancer (TNBC). Emerging agents targeting these signals offer the possibility to design new combinatorial therapies. However, preclinical models that recapitulate TNBC primary resistance and heterogeneity are essential to evaluate the potency of these combined treatments. Methods: Bioinformatic processing of human breast cancer datasets was used to analyse correlations between expression levels of cell cycle regulators and patient survival outcome. The MMTV-R26Met mouse model of TNBC resistance and heterogeneity was employed to analyse expression and targeting vulnerability of cell cycle regulators in the presence of BCL-XL blockage. Robustness of outcomes and selectivity was further explored using a panel of human breast cancer cells. Orthotopic studies in nude mice were applied for preclinical evaluation of efficacy and toxicity. Alterations of protein expression, phosphorylation, and/or cellular localisation were analysed by western blots, reverse phase protein array, and immunocytochemistry. Bioinformatics was performed to highlight drug's mechanisms of action. Results: We report that high expression levels of the BCL2L1 gene encoding BCL-XL and of specific cell cycle regulators correlate with poor survival outcomes of TNBC patients. Blockage of BCL-XL confers vulnerability to drugs targeting CDK1/2/4, but not FOXM1, CDK4/6, Aurora A and Aurora B, to all MMTV-R26Met and human TNBC cell lines tested. Combined blockage of BCL-XL and CDK1/2/4 interfered with tumour growth in vivo. Mechanistically, we show that, co-targeting of BCL-XL and CDK1/2/4 synergistically inhibited cell viability by combinatorial depletion of survival and RTK/AKT signals, and concomitantly restoring FOXO3a tumour suppression actions. This was accompanied by an accumulation of DNA damage and consequently apoptosis. Conclusions: Our studies illustrate the possibility to exploit the vulnerability of TNBC cells to CDK1/2/4 inhibition by targeting BCL-XL. Moreover, they underline that specificity matters in targeting cell cycle regulators for combinatorial anticancer therapies.

    Original languageEnglish (US)
    Pages (from-to)9180-9197
    Number of pages18
    JournalTheranostics
    Volume11
    Issue number19
    DOIs
    StatePublished - 2021

    Keywords

    • BCL-XL
    • Cancer mouse model
    • Cell cycle regulators
    • MET
    • Triple-negative breast cancer

    ASJC Scopus subject areas

    • Medicine (miscellaneous)
    • Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

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