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

Abstract

INTRODUCTIONMismatch 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.METHODSWe engineered glioblastoma cell lines and patient-derived glioblastoma neurosphere lines to knockdown MSH6 expression, resulting in acquired MMR-deficient resistance to TMZ. We treated these isogenic pairs of MSH6 wild type and MSH6-inactivated cells with TMZ, PARPi Veriparib or Olaparib, and combination. Using MSH6-deficient glioma xenografts, we tested the in vivo efficacy of veliparib in combination with TMZ. We used genetic and pharmacological approaches to assess the role of BER pathway in PARPi-mediated effects.RESULTSWe found that combination with PARPi restored TMZ sensitivity in MSH6-inactivated TMZ resistant cells whereas only subtle combination effects were seen in control MMR-proficient cells at the same PARPi concentrations. In vivo, combination treatment of TMZ with Veliparib demonstrated potent suppression of tumor growth of MSH6-inactivated orthotopic and flank xenografts, compared with TMZ monotherapy. Unlike PARPi, genetic and pharmacological blockage of BER pathway did not re-sensitize MSH6-inactivated cells to TMZ.CONCLUSIONPARPis restore TMZ sensitivity in MSH6-deficient glioblastoma cells. This combination treatment is a promising strategy to target acquired chemoresistance caused by MMR deficiency.