In the United States, breast cancer is the second leading cause of cancer-related deaths. About 15% of all breast cancer cases are classified as a triple negative breast cancer (TNBC) subtype, which is defined by the lack of estrogen receptor, progesterone receptor and HER2. TNBC is highly aggressive, characterized by a poorer prognosis, a quicker relapse after chemotherapy and a higher rate of visceral metastasis. Cytotoxic chemotherapy is still a primary treatment regimen for patients with TNBC due to the lack of targets. FDA-approved drugs, such as paclitaxel, are effective in treating neoadjuvant, adjuvant, or metastatic TNBC, but intrinsic or acquired resistance to taxanes is commonly observed. VERU-111 is a novel, potent and orally bioavailable tubulin inhibitor that targets the colchicine-binding site with potent cytotoxicity, have improved aqueous solubility and overcome multidrug resistance, including P-gp overexpression. We evaluated the efficacy of VERU-111 in treating TNBC. VERU-111 showed significant cytotoxicity to TNBC cells in vitro. In addition, orally administered VERU-111 suppressed the growth of MDA-MB-231 xenografts in a dose-dependent manner with efficacies similar to paclitaxel, but without acute toxicity. VERU-111 significantly reduced metastases originating from the mammary fat pad and visceral metastasis in a separate experimental metastasis model. To better understand the effect of VERU-111 on taxane-resistant TNBC, we developed taxane-resistant TNBC cell sublines, namely MDA-MB-231/TxR, MDA-MB-468/TxR, SUM159/TxR, with acquired resistance by exposing paclitaxel continually. MTS assay confirmed that VERU-111 maintained the potency against all taxane-resistant sublines. We also found that VERU-111 arrested both MDA-MB-231 and MDA-MB-231/TxR cells at the G2-M checkpoint in a concentration-dependent manner and induced ultimate cell death. In addition, relative to paclitaxel, orally administered VERU-111 effectively inhibited the tumor growth in two aggressive taxane-resistant TNBC xenograft models, including a taxane-resistant PDX model. VERU-111, but not paclitaxel, significantly repressed the growth of preestablished axillary lymph node metastases and endpoint metastasis in mice bearing HCI-10-Luc2 xenografts, suggesting VERU-111 is a promising drug candidate for the treatment of taxane-resistant TNBC. Taken together, our data demonstrate that VERU-111 is a new generation of oral tubulin inhibitor that potently inhibits the growth of taxane-sensitive and taxane-resistant TNBC.
Citation Format: Wei Li, Shanshan Deng, Raya Krutilina, Duane Miller, Tiffany Seagroves. Veru-111 as an orally available tubulin inhibitor suppressing both taxane-sensitive and taxane-resistant triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-37.