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

Abstract

Triple-negative breast cancer (TNBC) accounts for approximately 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 concentrationdependent 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 into 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 preestablished 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.Results presented in this study demonstrate the efficacy of VERU-111 in vivo and provide strong rationale for future development of VERU-111 as an effective treatment for metastatic breast cancer.

The Tubulin Inhibitor VERU-111 in Combination With Vemurafenib Provides an Effective Treatment of Vemurafenib-Resistant A375 Melanoma

“…A375 cells are one of the most widely used and representative V600E mutant melanoma cells, and we have previously reported the anti-tumor efficiency of VERU-111 in many cancer types ( Kashyap et al, 2019 ; Deng et al, 2020 ; Kashyap et al, 2020 ; Mahmud et al, 2020 ) as well as the synergy of Vem in combination with ABI-274 in A375 Vem-resistant melanoma cells ( Wang et al, 2014 ). Herein, we investigate whether the combination of VERU-111 (ABI-274 derivative) with Vem can also overcome Vem-resistance in A375.…”

“…Although combinations of BRAF inhibitor with MEK or ERK inhibitors benefit Vem-resistant patients ( Atefi et al, 2011 ; Gadiot et al, 2013 ; Pulkkinen et al, 2020 ), half of the patients still gain resistance after 6–8 months. Intriguingly, some tubulin destabilizing agents reported previously by us targeting the colchicine-binding site showed promise to overcome Vem-resistance, paclitaxel-resistance in melanoma, breast cancer, lung cancer, prostate cancer, cervical cancer et al ( Wang et al, 2014 ; Guan et al, 2017 ; Arnst et al, 2018 ; Deng et al, 2020 ; Kashyap et al, 2020 ; Mahmud et al, 2020 ). In our previous studies, we have demonstrated that a tool tubulin inhibitor, ABI-274, showed strong synergistic efficacy in a Vem-resistant xenograft mouse model ( Wang et al, 2014 ).…”

“…ABI-274 is a tool compound developed in our lab as a potent tubulin inhibitor that binds to the colchicine binding site (Chen et al, 2010;Wang et al, 2018). Further structural optimization from ABI-274 led to VERU-111 (Figure 1A), which is orally available and much more potent and less toxic in several types of tumor models, including prostate cancer, melanoma, breast cancer, lung cancer, and pancreatic cancer (Chen et al, 2012;Deng et al, 2020;Kashyap et al, 2020;Mahmud et al, 2020 (Chen et al, 2020). VERU-111 has now been under Phase 1b/2 clinical trials for men with metastatic castration and androgen-blocking agent resistant prostate cancer (ClinicalTrials.gov Identifier: NCT03752099) and holds great promise to become an oral tubulin inhibitor targeting the colchicine binding site.…”

“…ABI-274 is a tool compound developed in our lab as a potent tubulin inhibitor that binds to the colchicine binding site ( Chen et al, 2010 ; Wang et al, 2018 ). Further structural optimization from ABI-274 led to VERU-111 ( Figure 1A ), which is orally available and much more potent and less toxic in several types of tumor models, including prostate cancer, melanoma, breast cancer, lung cancer, and pancreatic cancer ( Chen et al, 2012 ; Deng et al, 2020 ; Kashyap et al, 2020 ; Mahmud et al, 2020 ). As literature reported, the IC 50 of ABI-274 was 25.3 nM while IC 50 of VERU-111 was 8.2 nM in MDA-MB-231 breast cancer cell, and the IC 50 of ABI-274 was 18.7 nM while IC 50 of VERU-111 was 10.4 nM in A375 melanoma cell ( Chen et al, 2020 ).…”

Suppression of Long Non-Coding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1) Potentiates Cell Apoptosis and Drug Sensitivity to Taxanes and Adriamycin in Breast Cancer

“…Tax plays a significant role in the treatment of breast cancer at both early and advanced stages [ 4 ]. As standard chemotherapies to stabilize microtubules, the clinical effects of Tax are frequently restricted by drug resistance and neurotoxicity [ 5 ]. Adriamycin (Adr) is another important and frequently applied chemotherapy agent in the treatment of breast cancer, with 2 key mechanisms: DNA damage and generation of reactive oxygen species [ 6 ].…”