Cancers, Vol. 13, Pages 944: Identification and Validation of ERK5 as a DNA Damage Modulating Drug Target in Glioblastoma

Cancers, Vol. 13, Pages 944: Identification and Validation of ERK5 as a DNA Damage Modulating Drug Target in Glioblastoma Cancers doi: 10.3390/cancers13050944 Authors: 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 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 E...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research