Mismatch repair defects underlying temozolomide chemoresistance in recurrent glioblastomas

Abstract

Sequencing of recurrent glioblastomas post temozolomide (TMZ) chemotherapy revealed two cases with somatic inactivating mutations in the mismatch repair gene MSH6, accompanied by loss of protein expression and a unique “hypermutation” phenotype. We subsequently reported that MSH6 inactivation is relatively common and is also associated with rapid tumor growth during TMZ treatment. To address the hypothesis that inactivation of MSH6 is related to TMZ resistance, we have isolated glioblastoma cell cultures (Gli56 and Gli60) from the two index cases and are examining in vitro sensitivity to chemotherapeutic agents including TMZ. We will use fluorescent‐tagged lentiviral constructs to restore MSH6 expression and functions in these cells. We then plan to introduce MSH6 mutants to systematically dissect MSH6 structure and function. Preliminary results showed MSH6 re‐expression restored in vitro TMZ cytotoxicity in glioma cells with MSH6 inactivation. Inactivation of MSH6 in recurrent glioblastoma during alkylator treatment appears frequent and related to rapid tumor regrowth, and re‐introduction of wildtype and mutated MSH6 genes will enable examination of the role of mismatch repair in TMZ cytotoxicity.