CD133 Is Associated with Increased Melanoma Cell Survival after Multikinase Inhibition. (16th July 2019)

• Record Type: Journal Article
• Authors: Simbulan-Rosenthal, Cynthia M.; Gaur, Anirudh; Zhou, Hengbo; AbdusSamad, Maryam; Qin, Qing; Dougherty, Ryan; Aljehane, Leala; Kuo, Li-Wei; Vakili, Sahar; Karna, Kumari; Clark, Havens; McCarron, Edward; Rosenthal, Dean S.
• Other Names: Simeone Pasquale Guest Editor.
• Is Part Of: Journal of oncology. Volume 2019(2019)
• Publication Date: 2019-07-16
• Subjects: Oncology -- Research -- Periodicals; Tumors -- Periodicals; Neoplasms; Oncology -- Research; Tumors; Periodicals; Periodicals; 616.994
• DOI: 10.1155/2019/6486173
• Languages: English
• ISSNs: 1687-8450

Abstract

Abstract : FDA-approved kinase inhibitors are now used for melanoma, including combinations of the MEK inhibitor trametinib, and BRAF inhibitor dabrafenib for BRAFV600 mutations. NRAS-mutated cell lines are also sensitive to MEK inhibition in vitro, and NRAS-mutated tumors have also shown partial response to MEK inhibitors. However, melanoma still has high recurrence rates due to subpopulations, sometimes described as "melanoma initiating cells, " resistant to treatment. Since CD133 is a putative cancer stem cell marker for different cancers, associated with decreased survival, we examined resistance of patient-derived CD133(+) and CD133(-) melanoma cells to MAPK inhibitors. Human melanoma cells were exposed to increasing concentrations of trametinib and/or dabrafenib, either before or after separation into CD133(+) and CD133(-) subpopulations. In parental CD133-mixed lines, the percentages of CD133(+) cells increased significantly (p<0.05) after high-dose drug treatment. Presorted CD133(+) cells also exhibited significantly greater (p<0.05) IC50s for single and combination MAPKI treatment. siRNA knockdown revealed a causal relationship between CD133 and drug resistance. Microarray and qRT-PCR analyses revealed that ten of 18 ABC transporter genes were significantly (P<0.05) upregulated in the CD133(+) subpopulation, while inhibition of ABC activity increased sensitivity, suggesting a mechanism for increased drug resistance of CD133(+) cells.