Abstract 4678: Targeting MEK in EGFR amplified glioma stem like cells induces differentiation

Abstract

Abstract The median survival for patients with recurrent glioblastoma is nine to twelve months highlighting the need for better therapeutic strategies for this deadly disease. The revolution in cancer genomics has identified multiple amplification events as potential targets for therapeutic intervention in many cancers including glioblastoma. Multiple factors such as incorrect patient selection, inadequate drug delivery across the blood brain barrier, acquired resistance and drug-target heterogeneity may all lead to clinical failure of targeted therapies. Receptor tyrosine kinase (RTK) signaling mediated by EGFR and PDGFR account for the core RTK signaling alterations in glioblastoma. EGFR-amplification (in ~40%) and PDGFR amplification (in ~12%) are detected in receptor tyrosine kinase- dysregulated glioblastoma. The first generation or second-generation EGFR tyrosine kinase small molecule inhibitors failed to show long term therapeutic benefit in glioblastoma patients. Through an unbiased high-throughput screen utilizing our glioma stem-like cells (GSCs) we identified that glioblastoma cells harboring EGFR amplification are uniquely vulnerable to mitogen-activated protein kinase (MEK) inhibitors. MEK inhibition induces apoptosis in EGFR amplified cells at low concentration. Furthermore, RNA sequence analysis of MEK inhibition revealed upregulation of genes related to differentiation in MEK sensitive glioma stem cells. Based upon these in vitro studies we are currently investigating MEK inhibition in a GBM xenograft mouse model. Overall our data suggest that the MEK inhibition could be a potential therapeutic target in a selective group of glioblastoma patients. Note: This abstract was not presented at the meeting. Citation Format: Soon Young Park, Yuji Piao, Emmanuel Martinez-Ledesma, Jianwen Dong, Sabbir Khan, Sandeep Mittal, Ze-yan Zhang, Erik P. Sulman, Veerakumar Balasubramaniyan, John F. de Groot. Targeting MEK in EGFR amplified glioma stem like cells induces differentiation [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 4678.