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 being diagnosed as high-grade malignancies known glioblastomas. Despite de-bulking surgery combined chemo-/radiotherapy regimens, the mean survival for these patients is only around 15 months, less 10% surviving over 5 years. This dismal prognosis highlights urgent need to develop novel agents improve treatment tumours. To address this need, we carried out a human kinome siRNA screen identify potential drug targets that augment effectiveness temozolomide (TMZ)—the standard-of-care chemotherapeutic agent used treat glioblastoma. From identified ERK5/MAPK7, which subsequently validated using range small molecule inhibitors within panel glioma cells. Mechanistically, find ERK5 promotes efficient repair TMZ-induced DNA lesions confer cell clonogenic capacity. Finally, several glioblastoma patient cohorts provide target validation data target, revealing heightened expression at both mRNA protein level associated increased tumour grade poorer survival. Collectively, findings foundation clinically effective targeting strategies in glioblastomas establish much-needed enhancement therapeutic repertoire currently incurable disease.