RSK2 activity mediates glioblastoma invasiveness and is a potential target for new therapeutics.
In glioblastoma (GBM), infiltration of primary tumor cells into the normal tissue and dispersal throughout the brain is a central challenge to successful treatment that remains unmet. Indeed, patients respond poorly to the current therapies of tumor resection followed by chemotherapy with radiotherapy and have only a 16-month median survival. It is therefore imperative to develop novel therapies. RSK2 is a kinase that regulates proliferation and adhesion and can promote metastasis. We demonstrate that active RSK2 regulates GBM cell adhesion and is essential for cell motility and invasion of patient-derived GBM neurospheres. RSK2 control of adhesion and migration is mediated in part by its effects on integrin-Filamin A complexes. Importantly, inhibition of RSK2 by either RSK inhibitors or shRNA silencing impairs invasion and combining RSK2 inhibitors with temozolomide improves efficacy in vitro. In agreement with the in vitro data, using public datasets, we find that RSK2 is significantly upregulated in vivo in human GBM patient tumors, and that high RSK2 expression significantly correlates with advanced tumor stage and poor patient survival. Together, our data provide strong evidence that RSK inhibitors could enhance the effectiveness of existing GBM treatment, and support RSK2 targeting as a promising approach for novel GBM therapy.
Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Mānoa, Honolulu, HI 96813, USA.
Florian J
FJ
Sulzmaier
Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Mānoa, Honolulu, HI 96813, USA.
Shirley
S
Young-Robbins
Department of Translational Neuro-Oncology and Neuro-therapeutics, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA 90404, USA.
Pengfei
P
Jiang
Department of Pediatric Oncology, Erasmus University Medical Center, Rotterdam, 3015 GE, The Netherlands.
Dirk
D
Geerts
Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Mānoa, Honolulu, HI 96813, USA.
Amanda M
AM
Prechtl
Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Mānoa, Honolulu, HI 96813, USA.
Michelle L
ML
Matter
Department of Translational Neuro-Oncology and Neuro-therapeutics, John Wayne Cancer Institute at Providence Saint John's Health Center, Santa Monica, CA 90404, USA.
Santosh
S
Kesari
Cancer Biology Program, University of Hawaii Cancer Center, University of Hawaii at Mānoa, Honolulu, HI 96813, USA.
Joe W
JW
Ramos
D000328:Adult; D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D002448:Cell Adhesion / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D005909:Glioblastoma / Q000235:genetics / Q000473:pathology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009361:Neoplasm Invasiveness; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000502:physiology*
D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3
ERK; GBM; MAPK; RSK; glioblastoma; invasion