부산대학교 도서관

Simple Summary: Glioblastomas are high-grade brain tumours and are the most common form of malignancy arising in the brain. Patient survival has improved little over the last 40 years, highlighting an urgent unmet need for more effective treatments for these tumours. Current standard-of-care treatment involves surgical removal of as much of the tumour as possible followed by a course of chemo-/radiotherapy. The main chemotherapeutic drug used is called temozolomide, however even with this treatment regimen, the average patient survival following diagnosis is around 15 months. We have identified a protein called ERK5 which is present at higher levels in these high-grade brain tumours compared to normal brain tissue, and which is also associated with resistance to temozolomide and poor patient survival. Additionally, we show that targeting ERK5 in brain tumour cells can improve the effectiveness of temozolomide in killing these tumour cells and offers potential much-needed future clinical benefit to patients diagnosed with 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 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. [ABSTRACT FROM AUTHOR]