Abstract
Simple SummaryThe oncogenic transcription factor FOXM1 is overexpressed in many cancers and associated with poor patient outcomes. Hence, there is much interest in blocking FOXM1 activity in cancer. We used small molecule inhibitors of FOXM1 to understand how they impact gene regulatory networks in suppressing cancer cell survival and the rewiring of gene networks that occurs when breast cancer cells become resistant to these compounds. Resistant cells showed reversal of the expression of many genes in the FOXM1 network controlling cell cycle progression, DNA damage repair, and apoptosis and also enhanced inflammatory signaling and upregulated HER2 and EGFR pathways. Targeting some of these factors so as to reduce the inflammatory and growth factor-dominant state of the resistant cancer cells should offer promising approaches for suppressing cancer progression and improving treatment of breast cancer.Forkhead box M1 (FOXM1), an oncogenic transcription factor associated with aggressiveness and highly expressed in many cancers, is an emerging therapeutic target. Using novel 1,1-diarylethylene-diammonium small molecule FOXM1 inhibitors, we undertook transcriptomic, protein, and functional analyses to identify mechanisms by which these compounds impact breast cancer growth and survival, and the changes that occur in estrogen receptor (ERα)-positive and triple negative breast cancer cells that acquire resistance upon long-term treatment with the inhibitors. In sensitive cells, these compounds regulated FOXM1 gene networks controlling cell cycle progression, DNA damage repair, and apoptosis. Resistant cells showed transcriptional alterations that reversed the expression of many genes in the FOXM1 network and rewiring that enhanced inflammatory signaling and upregulated HER2 or EGFR growth factor pathways. ERα-positive breast cancer cells that developed resistance showed greatly reduced ERα levels and responsiveness to fulvestrant and a 10-fold increased sensitivity to lapatinib, suggesting that targeting rewired processes in the resistant state may provide benefits and prolong anticancer effectiveness. Improved understanding of how FOXM1 inhibitors suppress breast cancer and how cancer cells can defeat their effectiveness and acquire resistance should be helpful in directing further studies to move these agents towards translation into the clinic.
Highlights
Forkhead box M1 (FOXM1) is an oncogenic transcription factor associated with cancer aggressiveness and poor patient survival [1,2]
What is of note is that we observed that breast cancer cells with acquired resistance upregulate interferon signaling pathways and/or TNFα inflammatory signaling, as well as growth factor regulated pathways while downregulating estrogen receptor (ERα), which enable them to overcome the growth inhibition initially brought about by these compounds. These same resistance pathways are known to be altered when breast cancers become resistant to other cancer therapeutic agents such as CDK4/6 inhibitors, endocrine agents such as tamoxifen, or DNA damaging radiation or chemotherapies [12,13,14,15,16,17,18], our findings reveal that the FOXM1 inhibitors show some distinct differences in mechanisms of resistance
In order to understand the biological mechanisms important in the inhibition of breast cancer cell growth and progression by FOXM1 inhibitors, we studied ER-positive and triple negative breast cancer cells sensitive to FOXM1 inhibitors, and we developed long-term treated cells that acquired resistance to growth suppression by these inhibitors
Summary
FOXM1 is an oncogenic transcription factor associated with cancer aggressiveness and poor patient survival [1,2]. We have identified small molecule inhibitors of FOXM1 that suppress the activity of this protein and reduce the level of FOXM1 in breast cancer cells and tumors. These novel 1,1-diarylethylene-diammonium compounds bind directly to the FOXM1 protein and increase its proteasomal degradation. NB73 and NB115 compounds were synthesized after verification of FOXM1 target engagement and structural optimization of hits from a more than 130,000 member chemical library of compounds These diamine compounds were shown to reduce the level of FOXM1 mRNA and protein and to inhibit the same
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