Antitumor activity of Cetuximab in combination with Ixabepilone on triple negative breast cancer stem cells.
Antitumor activity of Cetuximab in combination with Ixabepilone on triple negative breast cancer stem cells.
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DOI：
10.1186/s13058-015-0662-4
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发表时间：
2016-01-12
期刊：
影响因子：
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通讯作者：
Chang JC
中科院分区：
文献类型：
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作者：
Tanei T;Choi DS;Rodriguez AA;Liang DH;Dobrolecki L;Ghosh M;Landis MD;Chang JC
开发针对治疗抗性三阴性乳腺癌（TNBC）细胞的新策略仍然是一个重大挑战。ErbB家族，包括表皮生长因子受体（EGFR），在转移、肿瘤发生、细胞增殖和耐药性中发挥关键作用。最近，这些特征已经与被分类为癌症干细胞（CSC）的细胞的小亚群相关联，所述癌症干细胞被认为负责肿瘤的起始和维持。伊沙匹隆是新一代的微管稳定剂，被认为比传统的紫杉烷类药物更有效。在此，我们旨在研究EGFR单克隆抗体西妥昔单抗联合伊沙匹隆是否比单独化疗更有效地消除TNBC中的CSC群体。使用代表性TNBC细胞系（MDA-MB-231和SUM 159）来评估乳腺CSC群体。我们使用荧光激活细胞分选仪分析（CD 44+和CD 24-/低，或Aldefluor+）和称为乳腺球形成效率（MSFE）的自我更新试验来测量体外西妥昔单抗或西妥昔单抗+伊沙匹隆治疗后CSC群体的大小。尽管细胞活力没有显著降低，但西妥昔单抗通过抑制自噬在体外和体内降低了乳腺癌细胞中的MSFE和CSC群体。此外，SUM 159和MDA-MB-231原位肿瘤显示对Centuximab或Ixabepilone单一疗法的部分响应;然而，当与Ixabepilone单独治疗相比时，组合治疗的效果仅在SUM 159肿瘤中显著（p <0.0001）。总体而言，我们的研究结果表明，西妥昔单抗的EGFR靶向治疗有效地减少了TNBC肿瘤中的CSC群体。然而，与伊沙匹隆的组合疗法可能仅在TNBC的一小部分中有效，从而阻碍了对靶向用于TNBC治疗的多个途径的替代方法的进一步研究。本文的在线版本（doi：10.1186/s13058-015-0662-4）包含补充材料，可供授权用户使用。
Developing novel strategies against treatment-resistant triple negative breast cancer (TNBC) cells remains a significant challenge. The ErbB family, including epidermal growth factor receptor (EGFR), plays key roles in metastasis, tumorigenesis, cell proliferation, and drug resistance. Recently, these characteristics have been linked to a small subpopulation of cells classified as cancer stem cells (CSC) which are believed to be responsible for tumor initiation and maintenance. Ixabepilone is a new generation microtubule-stabilizing agent, which has been expected to be more efficacious than conventional taxanes. Here we aim to investigate whether the EGFR monoclonal antibody Cetuximab, in combination with Ixabepilone, is more effective in eliminating CSC populations compared to chemotherapy alone in TNBC. Representative TNBC cell lines (MDA-MB-231 and SUM159) were used to evaluate breast CSC populations. We used fluorescence-activated cell sorter analysis (CD44+ and CD24-/low, or Aldefluor+) and a self-renewal assay called mammosphere formation efficiency (MSFE) to measure CSC population size after treatment with Cetuximab, or Cetuximab plus Ixabepilone in vitro. Although there was no significant decrease in cell viability, Cetuximab reduced MSFE and the CSC population in breast cancer cells in vitro and in vivo through inhibition of autophagy. Also, SUM159 and MDA-MB-231 orthotopic tumors demonstrated partial response to Centuximab or Ixabepilone monotherapy; however, the effect of the combination treatment was significant only in SUM159 tumors (p <0.0001), when compared to Ixabepilone alone. Overall, our findings demonstrate that EGFR-targeted therapy by Cetuximab effectively reduces the CSC population in TNBC tumors. However, combination therapy with Ixabepilone may be effective only in a small subset of TNBCs, warranting further investigation of alternative approaches to target multiple pathways for TNBC treatment. The online version of this article (doi:10.1186/s13058-015-0662-4) contains supplementary material, which is available to authorized users.