Abstract 3891: CD133 is Associated with Resistance of Melanoma to Multikinase Inhibition

Abstract Purpose: High-risk melanoma is a lethal cancer with a high recurrence rates and variable disease-free intervals, due to tumorigenic cell populations that are resistant to treatment. Prominin 1 (CD133) is a putative stem cell marker in a number of cancers, based on its expression in cells that possess greater tumorigenicity, motility and colony-forming ability in different types of cancer. Furthermore, Prominin 1 is highly expressed in late-stage metastatic melanoma showing its potential as a marker of a resistant cell population. Trametinib and dabrafenib are targeted kinase inhibitors recently approved by the FDA, and now widely used for treatment of melanoma, while the anthelmintic drug mebendazole, a multikinase inhibitor, also exhibits promising anticancer potential. The purpose of this study was to test the relative resistance of CD133+ and CD133- cells to these three agents, as well as to explore potential mechanisms underlying any differences. Design: Three melanoma cell lines with different kinase mutation profiles were exposed to increasing concentrations of trametinib, dabrafenib, or mebendazole alone, or in combination, either before or after separation into CD133-positive and CD133-negative populations. Cells were then assayed for cell viability and CD133-positivity. Microarray analysis was performed on CD133-positive and CD133-negative cells to explore potential differences in gene expression profiles. Result: In all parental cell lines, the percentages of the CD133-positive cells increased significantly (P<0.05) after high-dose drug treatment. The CD133-positive, drug resistant cells showed reduced proliferation until after the drug was removed. Correspondingly, the presorted CD133-positive population exhibited significantly higher (P<0.05) IC50s both for single and multidrug treatment. Microarray analysis revealed a significant (P<0.001, >1.5-fold) difference in expression of 265 genes in CD133-positive cells, including putative oncogenes such as POU5F1, NPM1, NES and MYC. Also, 10 of 18 ABC transporter genes were significantly (P<0.05) up-regulated in the CD133-positive population. Conclusion: Both purified and mixed population-derived CD133 positive cells are more resistant to the three kinase inhibitors. Upregulation of ABC transporter genes and/or oncogenes may contribute to the drug resistance of CD133-positive cells. Citation Format: Hengbo Zhou, Maryam Abdussamad, Amani Alomari, Anirudh Gaur, Cynthia S. Rosenthal, John L. Zapas, Dean S. Rosenthal. CD133 is associated with resistance of melanoma to multikinase inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3891. doi:10.1158/1538-7445.AM2014-3891