Abstract 4847: Investigating the impact of astrocytes on targeted therapy of melanoma brain metastases

Abstract

Abstract Metastatic melanoma is a devastating disease that leads to the development of brain metastases (MBMs) in 40-60% of patients. Upon diagnosis of brain metastases, patient overall survival is less than 6 months. Poor patient survival is believed to be due to resistance driven by the brain microenvironment. Collectively, these findings underscore the need for novel therapeutic strategies to improve the survival of patients with MBMs. Development of effective therapies relies on an understanding of the interaction between MBMs and different cell types within the brain microenvironment. Astrocytes are the most abundant cell type within the brain and interact with MBMs through direct and indirect mechanisms. Astrocyte interaction with MBMs alters MBM gene expression and promotes metastatic outgrowth and resistance to cytotoxic chemotherapies. Exactly how astrocytes alter MBM response to MAPK inhibition remains unclear. Using conditioned media from primary astrocytes, as well as co-culture of primary astrocytes with either the MBM cell line WM4265-2 or the primary melanoma cell line WM983B, we found that the interaction of melanoma cells with astrocytes increased melanoma sensitivity to MEK inhibition (MEKi). RNA sequencing of WM4265-2 and WM983B cell lines treated with the MEK inhibitor PD0325901 (PD901) showed significant up-regulation of the transcriptional regulator ID3, which is known to play a role in the resistance of melanoma to MAPK inhibition. Interestingly, astrocyte conditioned media prevented the upregulation of ID3. To validate this finding, we silenced ID3 in WM4265-2 and WM983B cell lines, and showed that knockdown of ID3 caused increased sensitivity to MEKi. These combined data support the premise that the increased response to PD901 in MBMs exposed to astrocytes is due to ID3 down-regulation. How ID3 modulates resistance to MAPK inhibition remains unclear. Elucidating the mechanism of ID3 mediated resistance to MEKi may uncover new avenues for improving the treatment of melanoma brain metastases. Citation Format: Joshua Parris, Subhasree Basu, Thibaut Barnoud, Yongkang Zhao, Peter Somboonsong, Qing Chen, Maureen Murphy. Investigating the impact of astrocytes on targeted therapy of melanoma brain metastases [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 4847.