Key molecular regulators of acquired radiation resistance in recurrent glioblastoma (GBM) are largely unknown with a dearth of accurate pre-clinical models. To address this, we generated 8 GBM patient-derived xenograft (PDX) models of acquired radiation therapy-selected (RTS) resistance compared with same-patient, treatment naïve (RTU) PDX. These unique models mimic the longitudinal evolution of patient recurrent tumors following serial radiation therapy. Indeed, while whole exome sequencing confirmed retention of major genomic alterations in the RTS lines, we did detect a chromosome 12q14 amplification that is associated with clinical GBM recurrence in two RTS models. A novel bioinformatics pipeline was applied to analyze phenotypic, transcriptomic and kinomic alterations, which identified long non-coding RNAs (lncRNAs) and targetable, PDX-specific kinases. We observed differential transcriptional enrichment of DNA damage repair (DDR) pathways in our RTS models which correlated with several lncRNAs. Global kinomic profiling separated RTU and RTS models, but pairwise analyses indicated that there are multiple molecular routes to acquired radiation-resistance. RTS model-specific kinases were identified and targeted with clinically relevant small molecule inhibitors (SMIs). This unique cohort of in vivo radiation therapy-selected patient-derived models will enable future preclinical therapeutic testing to help overcome the treatment resistance seen in GBM patients.
Christian T. Stackhouse, Joshua C. Anderson, Zongliang Yue, Thanh Nguyen, Nicholas J. Eustace, Catherine P. Langford, Jelai Wang, James R. Rowland IV, Chuan Xing, Fady M. Mikhail, Xiangqin Cui, Hasan Alrefai, Ryan E. Bash, Kevin J. Lee, Eddy S. Yang, Anita B. Hjelmeland, C. Ryan Miller, Jake Y. Chen, G. Yancey Gillespie, Christopher D. Willey