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

Temozolomide (TMZ) is a chemotherapeutic agent that adds mutagenic adducts to guanine and has been the first-line standard of care for the aggressive brain cancer glioblastoma (GBM) since 2005. Though initially beneficial, TMZ-resistance is universal and second-line interventions are an unmet clinical need. Here we took advantage of the well-defined 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 using whole-genome sequencing.