Abstract
The transcription factor FOXM1 is upregulated and overexpressed in aggressive, therapy-resistant forms of hormone receptor-positive and triple negative breast cancers, and is associated with less good patient survival. FOXM1 signaling is also a key driver in many other cancers. Here, we identify a new class of compounds effective in suppressing FOXM1 activity in breast cancers, and displaying good potency for antitumor efficacy. The compounds bind directly to FOXM1 and alter its proteolytic sensitivity, reduce the cellular level of FOXM1 protein by a proteasome- dependent process, and suppress breast cancer cell proliferation and cell cycle progression and increase apoptosis. RNA-seq and gene set enrichment analyses indicate that the compounds decrease expression of FOXM1-regulated genes and suppress gene ontologies under FOXM1 regulation. Several compounds have favorable pharmacokinetic properties and show good tumor suppression in preclinical breast tumor models. These compounds may be suitable for further clinical evaluation in targeting aggressive breast cancers driven by FOXM1.
Highlights
IntroductionThe transcription factor FOXM1 is overexpressed and amplified in many types of cancers and is a master regulator of cancer cell division, aggressiveness, and metastasis.[1,2,3,4,5,6,7,8] FOXM1 activity promotes all of the hallmarks of cancer, stimulating cell proliferation, genome instability, angiogenesis, and suppressing cell senescence.[9,10] FOXM1 action is associated with resistance to endocrine therapies in estrogen receptor (ER)positive breast cancers and with resistance to radiation and many chemotherapies in several subtypes of breast cancer, and as well in many other cancers.[6,11,12,13,14,15] We have shown that FOXM1 increases the cancer stem cell population, drives proliferation, motility and invasiveness, and therapy resistance, and we found that knockdown of FOXM1 in breast cancer cells could restore sensitivity to endocrine therapy.[15]
They were obtained after FOXM1 target engagement verification and structural optimization of initial hits from a local chemical library that were identified through cell-based assays of inhibition of breast cancer cell proliferation and FOXM1-regulated gene expression, described below
We used a panel of human breast cancer cell lines and the nontumorigenic MCF10A breast cell line that differed in their FOXM1 protein content to examine the effects of potential FOXM1 inhibitor compounds on cell proliferation
Summary
The transcription factor FOXM1 is overexpressed and amplified in many types of cancers and is a master regulator of cancer cell division, aggressiveness, and metastasis.[1,2,3,4,5,6,7,8] FOXM1 activity promotes all of the hallmarks of cancer, stimulating cell proliferation, genome instability, angiogenesis, and suppressing cell senescence.[9,10] FOXM1 action is associated with resistance to endocrine therapies in estrogen receptor (ER)positive breast cancers and with resistance to radiation and many chemotherapies in several subtypes of breast cancer, and as well in many other cancers.[6,11,12,13,14,15] We have shown that FOXM1 increases the cancer stem cell population, drives proliferation, motility and invasiveness, and therapy resistance, and we found that knockdown of FOXM1 in breast cancer cells could restore sensitivity to endocrine therapy.[15]. To meet this clinical need, we have focused on the development of compounds to suppress FOXM1 activities
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