Abstract 3710: The role of eIF4E in promoting melanoma cell proliferation and maintaining acquired resistance to Vemurafenib in melanoma

Abstract

Abstract In eukaryotic cells, mRNA translation is restricted by the translation initiation step, in which eIF4E has been regarded as a master regulator. Overexpression of eIF4E has been found in different cancer types; however, whether eIF4E is involved in melanoma tumorigenesis and resistance to standard of care in melanoma remains unclear. We hypothesize that eIF4E promotes melanoma cell proliferation and facilitates the development of acquired resistance to the B-raf inhibitor, Vemurafenib. From our preliminary data, we show that eIF4E is overexpressed in a panel of malignant melanoma cell lines compared to immortalized melanocytes Mel ST. By genetically knocking down eIF4E via siRNA, we can significantly repress the proliferation of a subset of melanoma cell lines and decrease the level of the eIF4E downstream target Cyclin D1. In addition, the B-raf inhibitor Vemurafenib can drastically inhibit 4EBP-1 phosphorylation in BRAFV600E melanoma cell lines, and further cap binding analysis confirmed that Vemurafenib stabilizes the eIF4E - 4EBP-1 association in these cell lines.. In contrast, 4EBP-1 is highly phosphorylated in all Vemurafenib resistant cell lines, compared to the parental A375, even in the presence of Vemurafenib. Furthermore, cap binding assay show that, unlike their parental counterpart, four out of six resistant lines exhibit weak eIF4E - 4EBP-1 association even in the presence of Vemurafenib. This may imply that more free eIF4E is available for cap-dependent translation initiation in Vemu resistant lines compared to the parental A375. Besides, eIF4E activity contributes to the proliferation of some melanoma cell lines with acquired resistance to Vemurafenib, since siRNA-silencing eIF4E decreases their proliferation. In conclusion, our data show that eIF4E promotes proliferation of some melanoma cell lines and may be involved in maintaining the survival of some melanoma cell lines with acquired vemurafenib resistance. These data suggest that therapeutically targeting eIF4E may be a viable means of inhibiting melanoma cell proliferation and overcoming Vemurafenib resistance. Citation Format: Yao Zhan, Michael S. Dahabieh, Filippa Pettersson, Monica C. Dobocan, Marie Noel M. Boutchou, Leon Van Kempen, Sonia V. del Rincon, Wilson H. Miller, Jr.. The role of eIF4E in promoting melanoma cell proliferation and maintaining acquired resistance to Vemurafenib in melanoma. [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 3710. doi:10.1158/1538-7445.AM2014-3710