SPDR-05 PARP INHIBITORS RESTORE TEMOZOLOMIDE SENSITIVITY IN MSH6-DEFICIENT TEMOZOLOMIDE-RESISTANT GLIOBLASTOMA CELLS

摘要

Mismatch repair (MMR) deficiency through MSH6 inactivation has been identified in approximately 25% of recurrent gliomas. This MMR deficiency represents a key molecular mechanism of acquired resistance to the alkylating chemotherapeutic agent temozolomide (TMZ). Potentiation of TMZ-induced cytotoxicity by PARP inhibitors (PARPi) has been reported in several cancers including gliomas. However, mechanisms that underlie the PARPi-mediated chemo-potentiation and biomarkers that predict benefit from this combination treatment have not been identified in gliomas. We investigated whether PARPis could restore TMZ sensitivity of MSH6-deficient chemoresistant gliomas and assessed the role of the base excision repair (BER) DNA damage repair pathway in PARPi-mediated effects.