Cross-resistance of cisplatin selected cells to anti-microtubule agents: Role of general survival mechanisms

  • Transl Oncol. 2021 Jan;14(1):100917. doi: 10.1016/j.tranon.2020.100917.
Ruchi P Patel  1 ,  Skyler Kuhn  2 ,  Da Yin  3 ,  Jordan M Hotz  4 ,  Frances A Maher  5 ,  Robert W Robey  6 ,  Michael M Gottesman  7 ,  Sachi Horibata  8
Affiliations
  • 1. Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr. Room 2112, Bethesda, MD, United States. Electronic address: [email protected].
  • 2. CCR Collaborative Bioinformatics Resource (CCBR), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States. Electronic address: [email protected].
  • 3. CCR Collaborative Bioinformatics Resource (CCBR), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States. Electronic address: [email protected].
  • 4. Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr. Room 2112, Bethesda, MD, United States. Electronic address: [email protected].
  • 5. Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr. Room 2112, Bethesda, MD, United States. Electronic address: [email protected].
  • 6. Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr. Room 2112, Bethesda, MD, United States. Electronic address: [email protected].
  • 7. Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr. Room 2112, Bethesda, MD, United States. Electronic address: [email protected].
  • 8. Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 37 Convent Dr. Room 2112, Bethesda, MD, United States. Electronic address: [email protected].
PMID: 33129114 DOI: 10.1016/j.tranon.2020.100917
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.

Keywords
Anti-microtubule drugs; Cisplatin; Drug resistance; NFκB; Ovarian cancer; TNF.
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