Therapeutic Gene Silencing of CKAP5 leads to lethality in genetically unstable cancer cells.

Abstract Cell mitosis is an attractive target for cancer therapy. Presently, anti-mitotic drugs are limited to tubulin binding agents and kinase inhibitors. While there is a long list of potential microtubule associated protein targets that play an important role in tubulin function, their therapeutic potential remains largely unexplored due to the lack of target specific agents. Herein, we explored the therapeutic potential of targeting Cytoskeleton Associated Protein 5 (CKAP5), an important microtubule-associated protein, with CKAP5 targeting siRNAs that are entrapped in lipid nanoparticles (LNPs). We have screened the effect of CKAP5 silencing in a panel of solid cancer cell lines and demonstrated that silencing CKAP5 specifically affects genetically unstable cell lines, among which a chemo-resistant ovarian cancer cell line is most susceptible. CKAP5 knockdown led to loss of EB3 comet dynamics followed by apoptosis. Finally, we demonstrated the therapeutic potential in an in-vivo ovarian cancer model, showing increased survival rate in CKAP5 silenced LNP treated group by 80 % (p<0.0001). Taken together, our results may ultimately be translated into novel therapeutic modality for Ovarian Cancer and be utilized for other types of cancers.