CKAP5 as a potential therapeutic target in Ovarian Cancer

Due to toxic effects of chemotherapy and development of chemo-resistance in Ovarian cancer, there is a constant search of new therapeutic targets. One of the target of interest is CKAP5, which is a microtubule associated protein. CKAP5 plays an important role in bicentric spindle formation and its depletion leads to formation of multicentric spindles. We analyzed the effect of CKAP5 depletion in a panel of 20 cell lines from various solid cancers by CKAP5siRNA encapsulated lipid nanoparticles (LNPs). Our data suggests that most of the Ovarian cancer cell lines were highly sensitive to CKAP5 depletion and there was a significant loss of cell survival. Interestingly one of the chemo resistant ovarian cancer cell line, NAR was most sensitive to CKAP5 depletion in our panel and was used further as our study model. We further looked into the mechanism of cell death in response to CKAP5 knock down. We observed significant increment in the number of cells with multicentric spindle and G2-M cell cycle arrest. Since CKAP5 effects the spindle assembly during cell division, testing the levels of spindle checkpoint genes showed upregulaion in response to CKAP5 depletion. Further the study was extended to in vivo xenograft model and biodistribution of cy5 labelled siRNA LNPs showed colocalization in the xenografted tumour tissue. Treatment with CKAP5siRNA LNPs showed significant decrease in CKAP5 expression in treated tissue as compared to control which was corroborated with the increased survival in treated group as compared to control groups. Our preliminary efficacy data suggests that CKAP5 knock down through LNPs led to significant decrease (10 folds) in the tumor size. 40 days of follow up post treatment showed tumor relapse in only 1 out of 5 CKAP5 siRNA treated mice. Our preliminary results suggest CKAP5 as a novel therapeutic target in Ovarian cancer.