Abstract 848: Netropsin blocks EMT of murine BRAF mutated melanoma cells

Abstract

Abstract Melanoma is the most aggressive and deadliest type of skin cancer due to its high propensity to metastasize. Despite current progress in the identification of promising drugs for treating melanoma, drug resistance has emerged as a serious issue indicating that novel therapeutic strategies may be required. It is well documented that the process of converting the epithelial tumorigenic cell to a mesenchymal phenotype, the epithelial-mesenchymal transition (EMT), is responsible for conferring an invasive phenotype to cancer cells. An EMT-like process has been shown to occur during melanoma progression. High-mobility-protein AT-hook 2 (HMGA2) is a multi-function transcription factor linked to oncogenesis and EMT in a variety of cancers. HMGA2 is a small DNA-binding protein with three “AT-hook” DNA-binding motifs that specifically recognize the minor groove of AT-rich DNA sequences. HMGA2 is significantly upregulated in human primary melanoma and metastases, including those with BRAF mutations. We accessed the potential application of netropsin, a potent inhibitor of HMGA2-DNA interactions, as an EMT blocking agent of BRAF mutated melanoma cells. Three murine melanoma cells lines that carry mutations in the BRAF gene and show resistance to vemurafenib (D4M, YUMM1.1, and YUMM1.7) were used. Cells were treated with EMT Inducing Media Supplement along with Netropsin and the expression of E-cadherin as well as their migratory behavior were evaluated. Netropsin treatment of EMT induced cells was not cytotoxic, prevented changes in cell morphology, maintained high levels of E-cadherin expression and decreased migratory behavior. All three cell lines express HMGA2 which continues to be expressed in the tumors resulting from subcutaneous injections in mice. YUMM1.1 cells showed the highest levels of expression of HMGA2 amongst the three cell lines. Interestingly, in our preliminary study only YUMM1.1-derived tumors generated overt metastasis in the lung 30 days after the injections. Altogether our data showed that Netropsin is capable of blocking EMT of murine BRAF mutated melanoma cells. The results of this study will contribute to the development of strategies to prevent EMT that may result in the implementation of more effective therapies to treat melanoma. Citation Format: Juliano Freitas, Fenfei Leng, Lidia Kos. Netropsin blocks EMT of murine BRAF mutated melanoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 848. doi:10.1158/1538-7445.AM2017-848