O06 TARGETING FOXM1 AS A NOVEL THERAPEUTIC STRATEGY FOR THE TREATMENT OF MSH6 DEFICIENT TEMOZOLOMIDE-RESISTANT GLIOBLASTOMA

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2014-10, Vol.16 (suppl 6), p.vi14-vi14
• Main Authors: Brierley, D. J., Locke, M., Merve, A., Marino, S., Martin, S. A.
• Format: Article
• Language: English
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/nou250.6

INTRODUCTION: Mutations in the DNA mismatch repair gene MSH6 can arise in glioblastoma cells during Temozolomide treatment and can mediate drug resistance. Recently, exploiting the concept of synthetic lethality has been proposed as a therapeutic strategy. METHOD & RESULTS: Based on this approach we have identified the thiazole antibiotic Thiostrepton as synthetically lethal with MSH6 deficiency in the presence of Temozolomide, in vitro and in vivo. Our data suggest that in the absence of MSH6, FOXM1, a target of Thiostrepton, is upregulated due to reduced FOXO1/FOXO3a transcriptional repression. This regulation is through an interaction of MSH6 with the TGF beta-transcriptional complex containing phosphorylated-SMAD2 and SMAD3, with their co-SMAD, SMAD4. CONCLUSION: We suggest a novel role for MSH6 in the regulation of FOXM1 levels via the TGF beta-FOXO signaling pathway, which can mediate resistance to Temozolomide. Inhibition of FOXM1 in MSH6-deficient tumours provides a novel therapeutic strategy for the treatment of Temozolomide-resistant disease.