PO-048 Therapeutic relevance of the cell cycle protein BORA in cancer

Abstract

IntroductionPolo-like kinase 1 (Plk1) is an attractive mitotic target to treat cancer. A variety of anti-Plk1 agents are presently in clinical trials with successful results. Nonetheless, the use of Plk1 ATP-competitive inhibitors have been associated to dose-limiting toxicity and low specificity. Hence, to find alternative strategies to target Plk1 with less adverse effects is paramount. We propose to target the C-terminal part of Plk1 by its main coactivator, BORA (Aurora Borealis) since BORA binds to the Plk1-PDB and changes Plk1’s conformational status to be active. BORA per se has been described as a regulator of spindle stability being essential for proper chromosome segregation and disorders in genomic integrity generate vulnerabilities that can be exploited therapeutically. In this regard, we aim to provide new insights into the mechanistic consequences of BORA inhibition in cancer as potential therapeutic tool.Material and methodsIn silico data was obtained from TCGA database. In vitro studies were carried out using ovarian cancer cell lines. Human tissue-samples were obtained from benign and ovarian cancer patients from Vall d’Hebron Hospital, Barcelona. A pre-clinical ex vivo model was established by using patient-derived ascitic cells grown in 3D conditions. For the in vivo study, SKOV3 cells were used for subcutaneous injection in NMRI mice. A whole transcriptome analysis was carried out in SKOV3 and in ascites from ovarian cancer patient.Results and discussionsIn silico data revealed that BORA is overexpressed in several types of cancers compared to normal tissues, particularly in lung, colon and ovarian cancer. Genes with significant correlation with BORA revealed a cluster of proteins involved in DNA repair. In ovarian cancer (characterised by a genomic chaos) human tissue-samples showed that BORA is overexpressed compared to benign samples, significantly higher in advance stages of the disease and correlated with poor survival. The downregulation of BORA impaired the proliferation associated to an increase in the apoptosis rate and a G2/M phase arrest. Gene expression profile of Bora-depleted cells shed light on the underlying pathways. In addition, a pre-clinical ex vivo model using patient ascitic cells showed that BORA ablation decreased the tumor-sphere forming capacity and spheroid viability, a phenotype reproduced in the in vivo model by a reduction in tumour growth.ConclusionTargeting Plk1 activity through its main co-activator BORA may represent a novel cell cycle-related approach to treat cancer.