Triple negative breast cancers (TNBCs), with negligible ER, PR expression and HER2 amplification are the most aggressive form of breast cancer (BC). Due to the high level of genomic instability, treatment of TNBC patients is one of the prevalent challenges faced in the clinics. CEP55, a key regulator of cytokinesis and its malfunction leads to multi-nucleation. The functional role of CEP55 is critically regulated via phosphorylation of CEP55 by ERK2/PLK1 at specific stages of mitosis, sanctioning it to localise to the midbody for accurate cytokinesis. Studies have demonstrated the association of CEP55 with multiple malignancies especially BC as over-expression of CEP55 mRNA is linked with worse BC prognosis and poor survival. We postulate that CEP55 dictates the fate of aneuploid cell population, which are heavily reliant on mitotic genes for tumour progression among aggressive BC, thus can be targeted for therapy development.
Using a series of in vitro studies in BC cell lines, we demonstrated that CEP55 depletion leads to unscheduled CDK1/Cyclin B activation and favour CDK1-Caspase 3-dependent mitotic catastrophe after sensitising cells to anti-mitotic drugs like PLK1 inhibitor (BI2536). We have demonstrated that CEP55 mRNA is transcriptionally controlled by ERK1/2 and to overcome lack of a specific small molecule inhibitor against CEP55, inhibition of MEK1/2 using the small molecule inhibitor selumetinib, can mimic depletion of CEP55 in vivo. Thus, we rationalised the usage of a MEK1/2 inhibitor to inhibit CEP55 in combination with anti-mitotic agent.
We observed that compared to normal like and receptor-positive BC cell lines with lower CEP55 level, the aggressive hormone receptor negative cell lines with higher expression of CEP55 demonstrated robust synthetic lethality. Using xenograft models, we validated synergism of MEK1/2 and PLK1 inhibition, results of which imitated the in vitro findings.
Collectively, we propose a novel treatment strategy of MEK1/2 -PLK1 dual combination for selectively targeting CEP55 over-expressing BC in the clinics.
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The author has declared no conflicts of interest.