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Poster display session

4473 - Synergistic inhibition of CEP55 induces mitotic catastrophe and specifically targets aggressive breast cancer

Date

11 Sep 2017

Session

Poster display session

Topics

Translational Research;  Breast Cancer

Presenters

Debottam Sinha

Citation

Annals of Oncology (2017) 28 (suppl_5): v573-v594. 10.1093/annonc/mdx390

Authors

D. Sinha, M. Kalimutho, A.J. Lopez, K.K. Khanna

Author affiliations

  • Cell And Molecular Biology, QIMR Berghofer Medical Research Institute, 4006 - Brisbane/AU
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Resources

Abstract 4473

Background

Triple negative breast cancers (TNBCs) are the most aggressive and profoundly heterogeneous form of breast cancer (BC), treatment of which is a prevalent challenge faced in clinics. CEP55, discovered first by our laboratory, is a key regulator of cytokinesis, error in which roots to multi-nucleation. Function of CEP55 is critically delimited by ERK2/PLK1 dependent phosphorylation, for accurate cytokinesis. Research has demonstrated connotation of CEP55 with numerous cancers including BC as higher CEP55 mRNA expression is allied to worse prognosis and poor survival. We hypothesised that, CEP55 controls fate of aneuploid cell population among aggressive BC that are heavily reliant on mitotic genes for tumour progression, thus can be targeted for therapy development.

Methods

Using in vitro studies we demonstrated that depletion of CEP55 sensitizes TNBC cells to anti-mitotic drugs like PLK1 inhibitor to induce CDK1-Caspase 3-dependent mitotic catastrophe due to unscheduled CDK1/Cyclin B activation. Also we showed ERK1/2 transcriptionally controls CEP55 hence inhibition of MEK1/2 using the small molecule inhibitor Selumetinib, can mimic depletion of CEP55 in vivo.

Results

We rationalised the usage of a MEK1/2 inhibitor in combination with a PLK1 inhibitor across a series of BC cell lines. We observed synthetic lethality among the aggressive hormone receptor negative lines with higher CEP55 expression compared to normal like and receptor positive lines with lower CEP55 level. The combination synergistically amplified apoptosis of aneuploid population via premature entry of these cells into mitosis in the presence of antimitotic drugs due to exhaustion of CEP55. We have also validated this synergistic effect of MEK1/2 and PLK1 inhibition using xenograft models, results of which imitated the in vitro findings.

Conclusions

We propose a novel treatment tactic of MEK1/2 -PLK1 dual combination for selectively targeting CEP55 over-expressing BC in the clinics.

Clinical trial identification

Legal entity responsible for the study

QIMR Berghofer Medical Research Institute

Funding

Cancer Council Queensland (CCQ) and National Health & Medical Research Council

Disclosure

All authors have declared no conflicts of interest.

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