Abstract 1274: Partial reprogramming of melanoma cells confers drug resistance and increased vulnerability to channel antagonists

Abstract

Abstract During melanoma progression, tumor cells undergo phenotypic switching, increasing melanoma plasticity and resistance to mitogen-activated protein kinase inhibitors (MAPKi). We propose a partial reprogramming model to target melanoma therapy resistance. Here we show that partially reprogrammed cells are a less proliferative and more dedifferentiated cell population, expressing a gene signature for stemness and suppressing melanocyte-specific markers. To investigate the development of resistance to MAPKi, cells were exposed to BRAF and MEK inhibitors. Partially reprogrammed cells become less sensitive to MAPKi, showing increased cell viability and decreased apoptosis. Based on genome expression data, we evaluated potential targets to restore sensitivity to MAPKi in partially reprogrammed cells. One of our candidates showed promising results by increasing apoptosis and differentiation after sequential treatment with BRAF and MEK inhibitors, in partially reprogrammed cells and human BRAFi-resistant cells. In summary, we show that partial reprogramming of melanoma cells is a feasible in vitro model to study resistance to MAPKi. Moreover, we suggest our candidate as a target to restore sensitivity of resistant cells to MAPKi which has significant clinical implications in the development of resistance to current treatments against melanoma. Citation Format: Karol Granados, Laura Hüser, Aniello Federico, Sachindra Sachindra, Gretchen Wolff, Viktor Umansky, Jochen Utikal. Partial reprogramming of melanoma cells confers drug resistance and increased vulnerability to channel antagonists [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1274.