TY - JOUR
T1 - Identification and Validation of ERK5 as a DNA Damage Modulating Drug Target in Glioblastoma
AU - Carmell, Natasha
AU - Rominiyi, Ola
AU - Myers, Katie N.
AU - McGarrity-Cottrell, Connor
AU - Vanderlinden, Aurelie
AU - Lad, Nikita
AU - Perroux-David, Eva
AU - Sherif, Amira
AU - Fernando, Malee
AU - Finegan, Katie
AU - Brown, Stephen
AU - Collis, Spencer
N1 - Funding Information:
Funding: This research was funded by a Faculty, Departmental and SInFoNiA cosponsored PhD studentship, which was supplemented by a consumable grant award from Yorkshire’s Brain Tu‐ mour Charity (formally Brain Tumour Research and Support Across Yorkshire) awarded to S.J.C.
Funding Information:
This research was funded by a Faculty, Departmental and SInFoNiA cosponsored PhD studentship, which was supplemented by a consumable grant award from Yorkshire?s Brain Tumour Charity (formally Brain Tumour Research and Support Across Yorkshire) awarded to S.J.C.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/3/1
Y1 - 2021/3/1
N2 - 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.
AB - 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.
KW - DNA damage
KW - ERK5
KW - Glioblastoma
KW - MAPK7
KW - Sensitisation
KW - Temozolomide
UR - https://www.mdpi.com/2072-6694/13/5/944
U2 - 10.3390/cancers13050944
DO - 10.3390/cancers13050944
M3 - Article
C2 - 33668183
SN - 2072-6694
VL - 13
SP - 1
EP - 14
JO - Cancers
JF - Cancers
IS - 5
M1 - 944
ER -