RT Journal Article
SR Electronic
T1 BCL-XL blockage in TNBC models confers vulnerability to inhibition of specific cell cycle regulators
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.03.16.435600
DO 10.1101/2021.03.16.435600
A1 Olivier Castellanet
A1 Fahmida Ahmad
A1 Yaron Vinik
A1 Gordon B. Mills
A1 Bianca Habermann
A1 Jean-Paul Borg
A1 Sima Lev
A1 Fabienne Lamballe
A1 Flavio Maina
YR 2021
UL http://biorxiv.org/content/early/2021/03/17/2021.03.16.435600.abstract
AB 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. 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 BCL-XL and 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. Mechanistically, we show that, co-targeting of BCL-XL and CDK1/2/4 synergistically inhibited cell growth 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.Competing Interest StatementThe authors have declared no competing interest.