Mitotic Exit dysfunction through the deregulation of APC/C characterizes cisplatin resistant state in epithelial ovarian cancer

Purpose: Acquired resistance to cisplatin is a major barrier to success in treatment of various cancers and understanding mitotic mechanisms unique to cisplatin resistant cancer cells can provide the basis for developing novel mitotic targeted therapies aimed at eradicating these cells. Experimental Design: Using cisplatin resistant models derived from primary patient epithelial ovarian cancer (EOC) cells, we have explored the status of mitotic exit mechanisms in cisplatin resistant cells. Results: We have uncovered an unexpected role of long-term cisplatin treatment in inducing mitotic exit vulnerability characterized by increased spindle checkpoint activity and functional dependency on Polo-like kinase 1 (PLK1) for mitotic exit in the presence of Anaphase Promoting Complex/Cyclosome (APC/C) dysfunction in a cisplatin resistant state. Accordingly, PLK1 inhibition decreased the survival of cisplatin resistant cells in-vitro and in-vivo, and exacerbated spindle checkpoint response in these cells. APC/C ^CDC20 inhibition increased sensitivity to pharmacologic PLK1 inhibition further confirming the existence of APC/C dysfunction cisplatin resistant cells. In addition, we uncovered that resistance to Volasertib, PLK1 inhibitor, is due to maintenance of cells with low PLK1 expression. Accordingly, stable PLK1 downregulation in cisplatin resistant cells induced tolerance to Volasertib. Conclusions: We provide the first evidence of APC/C dysfunction in cisplatin resistant state, suggesting that understanding APC/C functions in cisplatin resistant state could provide basis for developing novel mitotic exit based therapies to eradicate cisplatin resistant cancer cells. Our results also show that PLK1 down-regulation could underlie emergence of resistance to PLK1 targeted therapies in cancers.

from Cancer via ola Kala on Inoreader https://ift.tt/2IS8jIZ
via IFTTT