Temozolomide-induced guanine mutations create exploitable vulnerabilities of guanine-rich DNA and RNA regions in drug-resistant gliomas
Year: 2022
Type: article
Abstract: Temozolomide (TMZ) is a chemotherapeutic agent that has been the first-line standard of care for the aggressive brain cancer glioblastoma (GBM) since 2005. Although initially beneficial, TMZ resistance is universal and second-line interventions are an unmet clinical need. Here, we took advantage of the known mechanism of action of TMZ to target guanines (G) and investigated G-rich G-quadruplex (G4) and splice site changes that occur upon TMZ resistance. We report that TMZ-resistant GBM has guanine mutations that disrupt the G-rich DNA G4s and splice sites that lead to deregulated alternative splicing. These alterations create vulnerabilities, which are selectively targeted by either the G4-stabilizing drug TMPyP4 or a novel splicing kinase inhibitor of cdc2-like kinase. Last, we show that the G4 and RNA binding protein EWSR1 aggregates in the cytoplasm in TMZ-resistant GBM cells and patient samples. Together, our findings provide insight into targetable vulnerabilities of TMZ-resistant GBM and present cytoplasmic EWSR1 as a putative biomarker.
Source: Science Advances
Authors: Deanna M Tiek, Beril Erdogdu, Roham Razaghi, Lu Jin, Norah Sadowski, Carla Alamillo-Ferrer, J Robert Hogg, Bassem R Haddad, David H Drewry, Carrow I Wells, Julie E. Pickett, Xiao Song, Anshika Goenka, Bo Hu, Samuel L Goldlust, William J Zuercher, Mihaela Pertea, Winston Timp, Shi-Yuan Cheng, Rebecca B Riggins
Institutions: Northwestern University, Georgetown University Medical Center, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Georgetown Lombardi Comprehensive Cancer Center, Johns Hopkins University, University of North Carolina at Chapel Hill, National Institutes of Health, National Heart, Lung, and Blood Institute, UNC Lineberger Comprehensive Cancer Center, Hackensack University Medical Center
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,500
Funders: Georgetown University, Wellcome Trust, National Institutes of Health, National Human Genome Research Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Center for Advancing Translational Sciences
Awards: Tools for Accelerating R&D for Historically Understudied Protein Kinases, Biochemistry, Cellular and Molecular Biology Program, Direct nanopore detection of modified RNA to probe structure and dynamics, Illuminating Function of the Understudied Druggable Kinome, Role of Protein Methylation in Cell Mitosis and Glioblastoma, Targeting ATG4B to Treat Glioblastoma, Novel relationships of splicing factors in temozolomide-resistant glioblastoma, Cysteine Depletion-induced Ferroptosis as a Therapeutic Vulnerability i, G9000091604, G9000226715, Georgetown University Lombardi Comprehensive Cancer Center Support Grant, Targeting RNA Splicing in Glioma, Training Grant In Tumor Biology, Perivascular tissue models to overcome MGMT-mediated temozolomide resistance in glioblastoma
OpenAlex ID: W3215624238