Abstract 1977: KIFC1 is a potential target to prevent treatment resistance in prostate cancer

Metastatic prostate cancer remains incurable. Taxane-based chemotherapy used to be restricted to the hormone-resistant metastatic setting. Unfortunately, most patients with castration-resistant prostate cancer (CRPC) rapidly develop resistance to chemotherapy. Recently, two trials demonstrated increased survival in men with high-risk metastatic hormone-sensitive prostate cancer treated with adjuvant chemohormonal therapy. Polyploidy has been demonstrated in most types of tumors to some extent and proposed to drive tumor progression by increasing the potential for cellular transformation. However, whether this is a cause or a consequence of cancer remains unclear. Different molecular mechanism can lead to polyploidy, such as mitotic slippage, endo-replication or cell fusion. In cancer biology, it has been associated with epithelial-mesenchymal transition (EMT), as well as with gain of stem-like potential. Experiments with drug gradients in our engineered microfluidic device have shown docetaxel therapy leads to polyploidy with a stiff distribution pattern of heterogeneous cell populations across the gradient. Moreover, in these experiments we evidenced polyploidization events occurring concurrently with the development of drug resistance. To confirm these findings, we conducted experiments in conventional cell culture using different chemotherapeutic agents in several prostate cancer cell lines and confirmed the development of polyploidy was a common feature among them. Interestingly, this feature occurred at some extent for all drugs, independently of the mechanism of action of the drug tested. Recent publications demonstrated the association of multinucleation with chemotherapy, androgen-deprivation therapy and radiotherapy. Although the data supporting the association of polyploidy with resistance is extensive, the effects of these therapies on tumor heterogeneity remains unknown. Most polyploid cells undergo cell death due to a mitotic catastrophe subsequent to multipolar cell division, however a small percentage of them survive and produce viable progeny of chemotherapy resistant clones via asymmetric cell division by undergoing centrosome clustering mediated by KIFC1. In this work, we focus on the characterization of the subset of cells within the tumor population that leads to the polyploid phenotype, particularly the subpopulation with potential to reverse polyploidy and repopulate tumor heterogeneity after therapy. We hypothesize a subset of polyploid cells with stem-like features may be the reservoir of therapeutic resistance in cancer. Given KIFC1 is required for centrosome clustering and clinical data suggests its association with polyploidy, poor prognosis and previous taxane-therapy in prostate cancer, we studied KIFC1 as a potential target to prevent relapse after therapy. Citation Format: Gonzalo Torga, Ke-Chih Lin, Bernat Navarro Serer, Cathleen Nguyen, Robert H. Austin, Kenneth J. Pienta. KIFC1 is a potential target to prevent treatment resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1977.