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 wit...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical investigation
2022-08-01
|
| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.148717 |
| _version_ | 1797634401372209152 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Christian T. Stackhouse |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:08:18Z |
| format | Article |
| id | doaj.art-f06e9a8597724e01bcfa17bb759ec86f |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:08:18Z |
| publishDate | 2022-08-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-f06e9a8597724e01bcfa17bb759ec86f2023-11-07T16:24:28ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-08-01716An in vivo model of glioblastoma radiation resistance identifies long noncoding RNAs and targetable kinasesChristian T. StackhouseJoshua C. AndersonZongliang YueThanh NguyenNicholas J. EustaceCatherine P. LangfordJelai WangJames R. Rowland IVChuan XingFady M. MikhailXiangqin CuiHasan AlrefaiRyan E. BashKevin J. LeeEddy S. YangAnita B. HjelmelandC. Ryan MillerJake Y. ChenG. Yancey GillespieChristopher D. WilleyKey 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.https://doi.org/10.1172/jci.insight.148717Oncology |
| spellingShingle | 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 An in vivo model of glioblastoma radiation resistance identifies long noncoding RNAs and targetable kinases JCI Insight Oncology |
| title | An in vivo model of glioblastoma radiation resistance identifies long noncoding RNAs and targetable kinases |
| title_full | An in vivo model of glioblastoma radiation resistance identifies long noncoding RNAs and targetable kinases |
| title_fullStr | An in vivo model of glioblastoma radiation resistance identifies long noncoding RNAs and targetable kinases |
| title_full_unstemmed | An in vivo model of glioblastoma radiation resistance identifies long noncoding RNAs and targetable kinases |
| title_short | An in vivo model of glioblastoma radiation resistance identifies long noncoding RNAs and targetable kinases |
| title_sort | in vivo model of glioblastoma radiation resistance identifies long noncoding rnas and targetable kinases |
| topic | Oncology |
| url | https://doi.org/10.1172/jci.insight.148717 |
| work_keys_str_mv | AT christiantstackhouse aninvivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT joshuacanderson aninvivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT zongliangyue aninvivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT thanhnguyen aninvivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT nicholasjeustace aninvivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT catherineplangford aninvivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT jelaiwang aninvivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT jamesrrowlandiv aninvivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT chuanxing aninvivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT fadymmikhail aninvivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT xiangqincui aninvivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT hasanalrefai aninvivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT ryanebash aninvivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT kevinjlee aninvivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT eddysyang aninvivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT anitabhjelmeland aninvivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT cryanmiller aninvivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT jakeychen aninvivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT gyanceygillespie aninvivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT christopherdwilley aninvivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT christiantstackhouse invivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT joshuacanderson invivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT zongliangyue invivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT thanhnguyen invivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT nicholasjeustace invivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT catherineplangford invivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT jelaiwang invivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT jamesrrowlandiv invivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT chuanxing invivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT fadymmikhail invivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT xiangqincui invivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT hasanalrefai invivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT ryanebash invivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT kevinjlee invivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT eddysyang invivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT anitabhjelmeland invivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT cryanmiller invivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT jakeychen invivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT gyanceygillespie invivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases AT christopherdwilley invivomodelofglioblastomaradiationresistanceidentifieslongnoncodingrnasandtargetablekinases |