An in vivo model of glioblastoma radiation resistance identifies long noncoding RNAs and targetable kinases

Key molecular regulators of acquired radiation resistance in recurrent glioblastoma (GBM) are largely unknown, with a dearth of accurate preclinical 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-naive (radiation-sensitive, unselected; RTU) PDXs. These likely unique models mimic the longitudinal evolution of patient recurrent tumors following serial radiation therapy. Indeed, while whole-exome sequencing showed retention of major genomic alterations in the RTS lines, we did detect a chromosome 12q14 amplification that was associated with clinical GBM recurrence in 2 RTS models. A potentially novel bioinformatics pipeline was applied to analyze phenotypic, transcriptomic, and kinomic alterations, which identified long noncoding RNAs (lncRNAs) and targetable, PDX-specific kinases. We observed differential transcriptional enrichment of DNA damage repair 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. This cohort of in vivo RTS patient-derived models will enable future preclinical therapeutic testing to help overcome the treatment resistance seen in patients with GBM.

Automated summary

The key molecular regulators of acquired radiation resistance in recurrent glioblastoma (GBM) are largely unknown. In this study, patient-derived xenograft (PDX) models were generated to mimic the longitudinal evolution of patient recurrent tumors following radiation therapy. Whole-exome sequencing and bioinformatics analysis identified genomic alterations and kinomic alterations associated with acquired radiation resistance. The study also found multiple molecular routes to acquired radiation resistance and identified targetable kinases for potential therapeutic interventions. This research provides important insights into overcoming treatment resistance in GBM patients.