Abstract 4229: ATP-binding cassette transporter ABCG2/BCRP inhibition sensitizes CD133+ cells to MEK/BRAF inhibitors

• Published in: Cancer research (Chicago, Ill.) Ill.), 2015-08, Vol.75 (15_Supplement), p.4229-4229
• Main Author: Mohamad Pauzi, Abrar
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2015-4229

Melanoma is a highly aggressive type of skin cancer. Melanoma-initiating cells (MIC) have self-renewal capacity, are highly tumorigenic and have been identified using CD133, a cell surface marker consisting of a 5-transmembrane protein. After magnetic sorting with anti-CD133 beads, we determined that CD133+ populations were more resistant than CD133- cells to MEK/BRAF inhibitors, the latter of which are targeted therapies for melanoma currently in clinical trials. In a microarray study, we found that the ABCG2 transporter is upregulated in the CD133+ MIC subpopulations. ABCG2, also known as breast cancer resistant protein (BCRP), is an ATP-binding cassette (ABC) transporter that facilitates the efflux of xenobiotics at the plasma membrane and is responsible for multidrug resistance in cancer cells. This study therefore aimed to block the ABCG2 transporter using the dual ABCG2/ABCB1 inhibitor elacridar to sensitize the CD133+ subpopulation to MEK/BRAF inhibitors. Three metastatic primary human melanoma cell lines were used to investigate the effects of inhibiting ABCG2 in drug-resistant CD133+ subpopulations. Elacridar was used for in vitro inhibition of ABCG2 prior to addition of single and combination treatments with trametinib (a MEK inhibitor), dabrafenib (a BRAF inhibitor), and mebendazole (an anthelmintic and possibly anticarcinogenic drug). Elacridar sensitized all treatment groups to drug treatment. Combination treatment using both ABCG2 and MEK/BRAF inhibitors at the lowest effective dose could be a potential therapeutic to eliminate the highly aggressive drug-resistant CD133+ MIC subpopulations. Citation Format: Abrar Mohamad Pauzi. ATP-binding cassette transporter ABCG2/BCRP inhibition sensitizes CD133+ cells to MEK/BRAF inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4229. doi:10.1158/1538-7445.AM2015-4229