Temozolomide-induced guanine mutations create exploitable vulnerabilities of guanine-rich DNA and RNA regions in drug-resistant gliomas.
Deanna Marie TiekBeril ErdogduRoham RazaghiLu JinNorah SadowskiCarla Alamillo-FerrerJ Robert HoggBassem R HaddadDavid Harold DrewryCarrow I WellsJulie E PickettXiao SongAnshika GoenkaBo HuSamuel A GoldlustWilliam J ZuercherMihaela PerteaWinston TimpShi-Yuan ChengRebecca B RigginsPublished in: Science advances (2022)
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.
Keyphrases
- drug resistant
- binding protein
- multidrug resistant
- healthcare
- nucleic acid
- induced apoptosis
- acinetobacter baumannii
- cell free
- palliative care
- single molecule
- case report
- newly diagnosed
- signaling pathway
- squamous cell
- emergency department
- squamous cell carcinoma
- cancer therapy
- high grade
- tyrosine kinase
- quality improvement
- cell cycle arrest
- atomic force microscopy
- white matter
- cell death
- blood brain barrier
- diabetic rats
- endoplasmic reticulum stress
- circulating tumor cells
- adverse drug
- electronic health record
- endothelial cells
- high speed