Temozolomide-induced guanine mutations create exploitable vulnerabilities of guanine-rich DNA and RNA regions in drug-resistant gliomas

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 A. Goldlust, William J. Zuercher, Mihaela Pertea, Winston Timp, Shi Yuan Cheng, Rebecca B. Riggins

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6 Scopus citations

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.

Original languageEnglish (US)
Article numbereabn3471
JournalScience Advances
Volume8
Issue number25
DOIs
StatePublished - Jun 2022
Externally publishedYes

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