DRES-19. THE MECHANISMS OF RESISTANCE TO TEMOZOLOMIDE IN GLIOMA CELLS

Abstract

Glioblastoma is one of the most aggressive tumors in the central nervous system tumors, with 5-year survival rates of less than 10%. The standard therapy for glioblastomas is maximal safe resection, followed by radiation therapy and chemotherapy with temozolomide (TMZ). One of the reasons of the worse prognosis is the acquisition of resistance to TMZ. TMZ is a DNA-methylating agent, delivering a methyl group to DNA (O6-guanine, N7-guanine and N3-adenine). The primary cytotoxic lesion, O6-methylguanine, mispairs with thymine, leading to futile DNA mismatch repair (MMR), formation of double strand breaks and eventual cell death, in the absence of O6-methylguanine DNA methyltransferase (MGMT). To clarify the mechanisms of resistance to TMZ and to find the way to overcome the resistance to TMZ, several clones of TMZ-resistant U251 were obtained and analyzed. #3 clone showed G2 arrest after TMZ exposure and this arrest was abrogated sooner compared to parental U251. TMZ did not induce G2 arrest in #8 clone. The expression of MGMT was not found in U251 parental cells, #3 cells nor #8 cells. The ability of homologous recombination (HR) was increased in #3 clone, and by suppression of HR, #3 resistant clone was resensitized to TMZ, however #8 was not. The protein levels of MSH6, which was associated with MMR, was reduced in #8 clone. PARP inhibitor resensitized #8 clone to TMZ, inducing apoptosis. Inhibition of HR or base excision repair was suggested to be a useful strategy to resensitize TMZ-resistant gliomas with higher HR or with MMR dysfunction to TMZ, respectively.