Targeting FOXM1 as a therapeutic strategy in cancer
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The transcription factor Forkhead Box Protein M1 (FOXM1) regulates several genes involved in the cell cycle, DNA repair, and oxidative stress, and is frequently upregulated in cancer cells. Whilst targeting FOXM1 alone represents an attractive treatment strategy, emergence of drug resistance makes a combination treatment strategy more clinically relevant. To investigate novel combination treatments with FOXM1 inhibition, we aimed to exploit the role of FOXM1 in regulating genes involved in the DNA repair pathway, homologous recombination. We hypothesised that reduction of homologous recombination due to FOXM1 inhibition, would render cancer cells synthetically lethal to PARP inhibition. Our data showed the FOXM1 inhibitor Thiostrepton and the PARP inhibitor Olaparib in combination caused greater reduction in cell viability, compared to either agent alone, in breast cancer cells. Mechanistically, our data suggested that RAD51 and BRIP1 may play a role in mediating Olaparib sensitisation upon Thiostrepton treatment, due to increased DNA double-strand breaks in cells treated with our combination therapy. We also explored the possibility of exploiting the role of FOXM1 in regulating oxidative stress response genes as a combination therapeutic strategy. Our data suggested that FOXM1 and NQO1 may play a role in generating chemoresistance. Furthermore, cancer cells may have a threshold of expression of FOXM1 and NQO1 for viability, where loss of both resulted in the greatest reduction in viability in Ovcar4 ovarian cancer cells. Therapeutically, our data showed for the first time that the FOXM1 inhibitor Thiostrepton and the NQO1 inhibitor Diminutol in combination caused greater reduction in cell viability, compared to either agent alone, in ovarian cancer cells. Our data suggested that our combination therapy may act through different mechanisms, including increased DNA double-strand breaks and increased levels of reactive oxygen species. Overall, we showed that exploiting the role of FOXM1 as a transcription factor provides a means for therapeutically targeting FOXM1 in combination with drugs that are synthetically lethal with FOXM1 transcriptional target genes.
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