Cross-resistance of cisplatin selected cells to anti-microtubule agents: Role of general survival mechanisms
Ruchi P. Patel, Skyler A. Kuhn, Da Yin, Jordan M. Hotz, Frances A. Maher, Robert W. Robey, Michael M. Gottesman, Sachi Horibata
Abstract
Although the first line of therapy for epithelial ovarian cancer typically consists of taxane-platinum combination therapy, many patients develop a platinum-resistant tumor within a year. Several previous studies have looked at this cross-resistance between cisplatin and anti-microtubule drugs, but their findings have been somewhat conflicting. Here, we developed cisplatin-resistant cell lines that are resistant to low and high levels of cisplatin and explored the effects of three anti-microtubule drugs (paclitaxel, vincristine, and colchicine) on the parental and cisplatin-resistant cells. We found that cells resistant to lower levels of cisplatin were no more resistant to anti-microtubule drugs than parental cells, while cells that were resistant to higher levels of cisplatin had a subpopulation of cells that were cross-resistant to anti-microtubule drugs, clarifying discrepancies within the field. We then isolated this subpopulation by applying selective pressure with anti-microtubule drugs and performed RNA sequencing and gene set enrichment analysis to identify resistance mechanisms. This subpopulation was found to express increased levels of pro-survival TNF/NFκB signaling, among other enriched pathways, suggesting that cross-resistance was due to more general survival mechanisms found in the cisplatin-selected cells.