An Orally Available Tubulin Inhibitor, VERU-111, Suppresses Triple-Negative Breast Cancer Tumor Growth and Metastasis and Bypasses Taxane Resistance.

Published on Feb 1, 2020in Molecular Cancer Therapeutics5.615
· DOI :10.1158/1535-7163.MCT-19-0536
Shanshan Deng5
Estimated H-index: 5
(UTHSC: University of Tennessee Health Science Center),
Raisa Krutilina8
Estimated H-index: 8
(UTHSC: University of Tennessee Health Science Center)
+ 7 AuthorsWei Li54
Estimated H-index: 54
(UTHSC: University of Tennessee Health Science Center)
Sources
Abstract
Triple-negative breast cancer (TNBC) accounts for ~15% of breast cancer cases in the United States. TNBC has poorer overall prognosis relative to other molecular subtypes due to rapid onset of drug resistance to conventional chemotherapies and increased risk of visceral metastases. Taxanes like paclitaxel are standard chemotherapies that stabilize microtubules, but their clinical efficacy is often limited by drug resistance and neurotoxicities. We evaluated the preclinical efficacy of a novel, potent and orally bioavailable tubulin inhibitor, VERU-111, in TNBC models. VERU-111 showed potent cytotoxicity against TNBC cell lines, inducing apoptosis and cell cycle arrest in a concentration-dependent manner. VERU-111 also efficiently inhibited colony formation, cell migration and invasion. Orally administered VERU-111 inhibited MDA-MB-231 xenograft growth in a dose-dependent manner, with similar efficacies to paclitaxel, but without acute toxicity. VERU-111 significantly reduced metastases originating from the mammary fat pad and lung, liver and kidney metastasis in an experimental metastasis model. Moreover, VERU-111, but not paclitaxel, suppressed growth of luciferase-labeled, taxane-resistant patient-derived metastatic TNBC tumors. In this model, VERU-111 repressed growth of pre-established axillary lymph node metastases and lung, bone and liver metastases at study endpoint, whereas paclitaxel enhanced liver metastases relative to vehicle controls. Collectively, these studies strongly suggest that VERU-111 is not only a potent inhibitor of aggressive TNBC phenotypes, but it is also efficacious in a taxane-resistant model of metastatic TNBC. Thus, VERU-111 is a promising new generation of tubulin inhibitor for the treatment of TNBC and may be effective in patients who progress on taxanes.
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