Abstract 642: Flavopiridol inhibits cell proliferation, migration, and invasion via downregulation of FOXM1 in triple negative breast cancer

Abstract

Abstract Triple-negative breast cancer (TNBC) represent 15-20% of all breast cancers and is the subtype of breast cancer that is not responsive to targeted breast cancer treatments such as anti-estrogens (tamoxifen) or HER2 targeted antibodies due to the lack of ER, PR, and HER2 receptors. TNBC is associated with poor prognosis, early relapse, and distant metastasis and drug resistance. With the use of standard chemotherapeutics in the neoadjuvant setting, unfortunately the majority of patients (~60%) with TNBC do not achieve complete remission and 40% of the patients with regional (Stage II) and 90% of the patients with distant metastasis (Stage IV) die within 5-years. Currently, there is no effective targeted therapy for TNBC patients for targeting oncogenic pathways. Although recently the FDA approved sacituzumab (govitecan), a Trop-2-receptor directed antibody conjugated with chemotherapeutic agent topoisomerase inhibitor in metastatic TNBC, and response rate was 30% and the median duration of response is 7.7 months, and the majority of patients did not maintain response longer than 12 months. Therefore, identifying novel molecular targets and developing alternative therapeutic strategies are urgently needed. FOXM1 is a protooncogenic transcription factor suppressed by p53 and drives expression of genes, which play a crucial role in promoting cancer cell proliferation, metastasis, progression, tumorigenesis of TNBC. We previously demonstrated for the first time that in vivo targeting of FOXM1 suppresses TNBC tumor growth in mice. Here, analyzing TCGA patient database we found that FOXM1 expression correlates with shorter patient survival and prognosis in TNBC patients. Overall data suggest that FOXM1 is a potential molecular target. However, currently, there is no FDA approved inhibitor of FOXM1. To identify potential inhibitors, utilizing silico docking and molecular dynamics studies we screened the FDA-approved compounds found that flavopiridol interacts with FOXM1. Flavopiridol is a small molecule inhibitor for CDKs and is approved by the FDA for the treatment of Acute Myeloid Leukemia. We demonstrated that flavodilol inhibits FOXM1 expression at nanomolar concentration and cell proliferation, migration, invasion, and induces apoptosis in TNBC cells. We are currently testing favopridol in MDA-MB-231 (human) and 4T1 mouse mammary) TNBC tumor models. In conclusion, our studies suggest that flavopiridol is a highly potent FOXM1 inhibitor and is a promising agent for repurposing to target FOXM1 and for the treatment of TNBC. Citation Format: Sayra Dilmac, Nermin Kahraman, Ferah Comert Onder, Zuhal Hamurcu, Bulent Ozpolat. Flavopiridol inhibits cell proliferation, migration, and invasion via downregulation of FOXM1 in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 642.