Abstract 1634: Reduction or loss of Msh2 confers resistance to temozolomide in glioblastoma

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor. The only intervention that has improved the survival rate of GBM patients over the past several decades has been combining temozolomide (TMZ) with radiotherapy (RT), which increased median survival by only ~2.5 months to where it currently stands at ~15 months. Unfortunately, all GBM patients eventually die due to tumor recurrence. Intrinsic or acquired resistance to TMZ is a significant contributing factor to tumor progression, and various mechanisms have been suggested, including deficiencies in DNA mismatch repair (MMR) genes such as MSH2. Utilizing patient GBM samples from the TCGA, we have identified a correlation between low MSH2 expression and shorter patient survival. To test the biological significance of Msh2 in GBM growth and resistance to TMZ and immunotherapy, we have generated immunocompetent genetically engineered mouse models (GEMMs) of GBM with germline or somatic loss of Msh2. To generate tumors with reduced or abrogated Msh2, we utilized GEMMs based on the RCAS/tv-a gene transfer system in combination with mice that exhibited heterozygous and homozygous loss of Msh2. When PDGFB was overexpressed in combination with the silencing of Tp53 to induce tumors, tumor-bearing mice with reduced or deficient Msh2 demonstrated shorter survival time compared to wild-type tumor-bearing mice. In addition, our results indicate Msh2 deficiency increases the malignancy of gliomas. Our data demonstrate that two weeks of TMZ treatment at a clinically relevant dose of 25 mg/kg provides a significant survival advantage in WT-tumor-bearing mice, while no efficacy was observed in tumor-bearing mice with either heterozygous or homozygous loss of Msh2. We are currently evaluating the role of Msh2 in the efficacy of immune checkpoint inhibitors in glioblastoma. Citation Format: Montserrat Puigdelloses Vallcorba, Alice Buonfiglioli, Gonzalo Piñero, Zhihong Chen, Dolores Hambardzumyan. Reduction or loss of Msh2 confers resistance to temozolomide in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1634.