An Orally Available Tubulin Inhibitor, VERU-111, Suppresses Triple-Negative Breast Cancer Tumor Growth and Metastasis and Bypasses Taxane Resistance
An Orally Available Tubulin Inhibitor, VERU-111, Suppresses Triple-Negative Breast Cancer Tumor Growth and Metastasis and Bypasses Taxane Resistance
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DOI：
10.1158/1535-7163.mct-19-0536
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发表时间：
2020-02-01
影响因子：
5.7
通讯作者：
Li, Wei
中科院分区：
文献类型：
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作者：
Deng, Shanshan;Krutilina, Raisa I.;Li, Wei
三阴性乳腺癌（TNBC）约占美国乳腺癌病例的15%。TNBC相对于其他分子亚型具有较差的总体预后，这是由于对常规化疗的耐药性的快速发作和内脏转移的风险增加。紫杉烷类如紫杉醇是稳定微管的标准化疗药物，但其临床疗效往往受到耐药性和神经毒性的限制。我们在TNBC模型中评估了一种新型的、有效的和口服生物可利用的微管蛋白抑制剂VERU-111的临床前功效。VERU-111对TNBC细胞系显示出强的细胞毒性，以浓度依赖性方式诱导细胞凋亡和细胞周期停滞。VERU-111还有效地抑制集落形成、细胞迁移和侵袭。口服给予VERU-111以剂量依赖性方式抑制MDA-MB-231异种移植物生长，具有与紫杉醇相似的功效，但没有急性毒性。在实验转移模型中，VERU-111显著减少了从乳腺脂肪垫转移到肺、肝和肾的转移。此外，VERU-111，而不是紫杉醇，抑制了脱氢酶标记的，紫杉烷耐药的，患者来源的转移性TNBC肿瘤的生长。在该模型中，VERU-111在研究终点抑制预先建立的腋窝淋巴结转移瘤以及肺、骨和肝转移瘤的生长，而紫杉醇相对于载体对照增强肝转移瘤。总的来说，这些研究强烈表明VERU-111不仅是侵袭性TNBC表型的有效抑制剂，而且在转移性TNBC的紫杉烷抗性模型中也是有效的。因此，VERU-111是一种有前途的新一代微管蛋白抑制剂，用于治疗TNBC，并可能是有效的患者谁进展的taxanes.Results在本研究中展示的VERU-111在体内的疗效和VERU-111作为一种有效的治疗转移性乳腺癌的未来发展提供了强有力的理由。
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 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 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.