Identification and Validation of ERK5 as a DNA Damage Modulating Drug Target in Glioblastoma
Brain tumours kill more children and adults under 40 than any other cancer, with approximately half of primary brain tumours being diagnosed as high-grade malignancies known as glioblastomas. Despite de-bulking surgery combined with chemo-/radiotherapy regimens, the mean survival for these patients...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-02-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/13/5/944 |
| _version_ | 1797395431495303168 |
|---|---|
| author | Natasha Carmell Ola Rominiyi Katie N. Myers Connor McGarrity-Cottrell Aurelie Vanderlinden Nikita Lad Eva Perroux-David Sherif F. El-Khamisy Malee Fernando Katherine G. Finegan Stephen Brown Spencer J. Collis |
| author_facet | Natasha Carmell Ola Rominiyi Katie N. Myers Connor McGarrity-Cottrell Aurelie Vanderlinden Nikita Lad Eva Perroux-David Sherif F. El-Khamisy Malee Fernando Katherine G. Finegan Stephen Brown Spencer J. Collis |
| author_sort | Natasha Carmell |
| collection | DOAJ |
| description | Brain tumours kill more children and adults under 40 than any other cancer, with approximately half of primary brain tumours being diagnosed as high-grade malignancies known as glioblastomas. Despite de-bulking surgery combined with chemo-/radiotherapy regimens, the mean survival for these patients is only around 15 months, with less than 10% surviving over 5 years. This dismal prognosis highlights the urgent need to develop novel agents to improve the treatment of these tumours. To address this need, we carried out a human kinome siRNA screen to identify potential drug targets that augment the effectiveness of temozolomide (TMZ)—the standard-of-care chemotherapeutic agent used to treat glioblastoma. From this we identified ERK5/MAPK7, which we subsequently validated using a range of siRNA and small molecule inhibitors within a panel of glioma cells. Mechanistically, we find that ERK5 promotes efficient repair of TMZ-induced DNA lesions to confer cell survival and clonogenic capacity. Finally, using several glioblastoma patient cohorts we provide target validation data for ERK5 as a novel drug target, revealing that heightened ERK5 expression at both the mRNA and protein level is associated with increased tumour grade and poorer patient survival. Collectively, these findings provide a foundation to develop clinically effective ERK5 targeting strategies in glioblastomas and establish much-needed enhancement of the therapeutic repertoire used to treat this currently incurable disease. |
| first_indexed | 2024-03-09T00:35:24Z |
| format | Article |
| id | doaj.art-5308aaf0e8fe45538e7686438f48d87c |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T00:35:24Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-5308aaf0e8fe45538e7686438f48d87c2023-12-11T18:13:25ZengMDPI AGCancers2072-66942021-02-0113594410.3390/cancers13050944Identification and Validation of ERK5 as a DNA Damage Modulating Drug Target in GlioblastomaNatasha Carmell0Ola Rominiyi1Katie N. Myers2Connor McGarrity-Cottrell3Aurelie Vanderlinden4Nikita Lad5Eva Perroux-David6Sherif F. El-Khamisy7Malee Fernando8Katherine G. Finegan9Stephen Brown10Spencer J. Collis11Weston Park Cancer Centre, Department of Oncology & Metabolism, The University of Sheffield Medical School, Sheffield S10 2SJ, UKWeston Park Cancer Centre, Department of Oncology & Metabolism, The University of Sheffield Medical School, Sheffield S10 2SJ, UKWeston Park Cancer Centre, Department of Oncology & Metabolism, The University of Sheffield Medical School, Sheffield S10 2SJ, UKWeston Park Cancer Centre, Department of Oncology & Metabolism, The University of Sheffield Medical School, Sheffield S10 2SJ, UKWeston Park Cancer Centre, Department of Oncology & Metabolism, The University of Sheffield Medical School, Sheffield S10 2SJ, UKWeston Park Cancer Centre, Department of Oncology & Metabolism, The University of Sheffield Medical School, Sheffield S10 2SJ, UKWeston Park Cancer Centre, Department of Oncology & Metabolism, The University of Sheffield Medical School, Sheffield S10 2SJ, UKSheffield Institute for Nucleic Acids (SInFoNiA) and the Healthy Lifespan Institute, University of Sheffield, Sheffield S10 2TN, UKDepartment of Histopathology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2TN, UKFaculty of Biology Medicine and Health, University of Manchester, Manchester M13 9PL, UKDepartment of Biomedical Science, The Sheffield RNAi Screening Facility, The University of Sheffield, Sheffield S10 2TN, UKWeston Park Cancer Centre, Department of Oncology & Metabolism, The University of Sheffield Medical School, Sheffield S10 2SJ, UKBrain tumours kill more children and adults under 40 than any other cancer, with approximately half of primary brain tumours being diagnosed as high-grade malignancies known as glioblastomas. Despite de-bulking surgery combined with chemo-/radiotherapy regimens, the mean survival for these patients is only around 15 months, with less than 10% surviving over 5 years. This dismal prognosis highlights the urgent need to develop novel agents to improve the treatment of these tumours. To address this need, we carried out a human kinome siRNA screen to identify potential drug targets that augment the effectiveness of temozolomide (TMZ)—the standard-of-care chemotherapeutic agent used to treat glioblastoma. From this we identified ERK5/MAPK7, which we subsequently validated using a range of siRNA and small molecule inhibitors within a panel of glioma cells. Mechanistically, we find that ERK5 promotes efficient repair of TMZ-induced DNA lesions to confer cell survival and clonogenic capacity. Finally, using several glioblastoma patient cohorts we provide target validation data for ERK5 as a novel drug target, revealing that heightened ERK5 expression at both the mRNA and protein level is associated with increased tumour grade and poorer patient survival. Collectively, these findings provide a foundation to develop clinically effective ERK5 targeting strategies in glioblastomas and establish much-needed enhancement of the therapeutic repertoire used to treat this currently incurable disease.https://www.mdpi.com/2072-6694/13/5/944ERK5MAPK7glioblastomatemozolomideDNA damagesensitisation |
| spellingShingle | Natasha Carmell Ola Rominiyi Katie N. Myers Connor McGarrity-Cottrell Aurelie Vanderlinden Nikita Lad Eva Perroux-David Sherif F. El-Khamisy Malee Fernando Katherine G. Finegan Stephen Brown Spencer J. Collis Identification and Validation of ERK5 as a DNA Damage Modulating Drug Target in Glioblastoma Cancers ERK5 MAPK7 glioblastoma temozolomide DNA damage sensitisation |
| title | Identification and Validation of ERK5 as a DNA Damage Modulating Drug Target in Glioblastoma |
| title_full | Identification and Validation of ERK5 as a DNA Damage Modulating Drug Target in Glioblastoma |
| title_fullStr | Identification and Validation of ERK5 as a DNA Damage Modulating Drug Target in Glioblastoma |
| title_full_unstemmed | Identification and Validation of ERK5 as a DNA Damage Modulating Drug Target in Glioblastoma |
| title_short | Identification and Validation of ERK5 as a DNA Damage Modulating Drug Target in Glioblastoma |
| title_sort | identification and validation of erk5 as a dna damage modulating drug target in glioblastoma |
| topic | ERK5 MAPK7 glioblastoma temozolomide DNA damage sensitisation |
| url | https://www.mdpi.com/2072-6694/13/5/944 |
| work_keys_str_mv | AT natashacarmell identificationandvalidationoferk5asadnadamagemodulatingdrugtargetinglioblastoma AT olarominiyi identificationandvalidationoferk5asadnadamagemodulatingdrugtargetinglioblastoma AT katienmyers identificationandvalidationoferk5asadnadamagemodulatingdrugtargetinglioblastoma AT connormcgarritycottrell identificationandvalidationoferk5asadnadamagemodulatingdrugtargetinglioblastoma AT aurelievanderlinden identificationandvalidationoferk5asadnadamagemodulatingdrugtargetinglioblastoma AT nikitalad identificationandvalidationoferk5asadnadamagemodulatingdrugtargetinglioblastoma AT evaperrouxdavid identificationandvalidationoferk5asadnadamagemodulatingdrugtargetinglioblastoma AT sheriffelkhamisy identificationandvalidationoferk5asadnadamagemodulatingdrugtargetinglioblastoma AT maleefernando identificationandvalidationoferk5asadnadamagemodulatingdrugtargetinglioblastoma AT katherinegfinegan identificationandvalidationoferk5asadnadamagemodulatingdrugtargetinglioblastoma AT stephenbrown identificationandvalidationoferk5asadnadamagemodulatingdrugtargetinglioblastoma AT spencerjcollis identificationandvalidationoferk5asadnadamagemodulatingdrugtargetinglioblastoma |