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An in vivo model of glioblastoma radiation resistance identifies long noncoding RNAs and targetable kinases
Christian T Stackhouse1,2, Joshua C Anderson2, Zongliang Yue3
1Department of Neurosurgery.
Abstract:
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.
Insights
Researchers developed new glioblastoma patient-derived xenograft models to study radiation resistance. These models reveal molecular pathways and potential drug targets for overcoming treatment resistance in recurrent brain tumors.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Acquired radiation resistance is a major challenge in treating recurrent glioblastoma (GBM).
- Accurate preclinical models are lacking to study the molecular mechanisms of radiation resistance in GBM.
- Understanding these mechanisms is crucial for developing effective therapies.
Purpose of the Study:
- To generate and characterize novel patient-derived xenograft (PDX) models of acquired radiation therapy-selected (RTS) resistance in glioblastoma.
- To identify key molecular regulators, including long noncoding RNAs (lncRNAs) and kinases, associated with radiation resistance.
- To provide a platform for preclinical testing of therapeutic strategies against resistant GBM.
Main Methods:
- Generation of 8 GBM patient-derived xenograft (PDX) models selected for acquired radiation resistance (RTS) and comparison with radiation-sensitive (RTU) counterparts.
- Whole-exome sequencing to analyze genomic alterations.
- Application of a novel bioinformatics pipeline for phenotypic, transcriptomic, and kinomic analyses.
- Global kinomic profiling and targeting of identified kinases with small molecule inhibitors.
Main Results:
- RTS models retained major genomic alterations but showed a chromosome 12q14 amplification in 2 models, linked to clinical recurrence.
- Identification of differentially expressed long noncoding RNAs (lncRNAs) and PDX-specific kinases.
- Enrichment of DNA damage repair pathways in RTS models, correlated with specific lncRNAs.
- Kinomic profiling revealed distinct molecular profiles for RTU and RTS models, indicating multiple resistance pathways.
- Targeting identified RTS model-specific kinases with inhibitors showed promise.
Conclusions:
- The developed RTS PDX models accurately mimic longitudinal tumor evolution following radiation therapy.
- These models have identified novel lncRNAs and targetable kinases involved in acquired radiation resistance in GBM.
- This preclinical cohort offers a valuable resource for evaluating new therapies to overcome glioblastoma treatment resistance.
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