Inhibition of chemotherapy resistant breast cancer stem cells by a ROR1 specific antibody
Inhibition of chemotherapy resistant breast cancer stem cells by a ROR1 specific antibody
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ROR1 特异性抗体抑制化疗耐药乳腺癌干细胞
DOI：
10.1073/pnas.1816262116
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发表时间：
2019-01-22
影响因子：
11.1
通讯作者：
Kipps, Thomas J.
中科院分区：
文献类型：
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作者：
Zhang, Suping;Zhang, Han;Kipps, Thomas J.
意义我们报道了紫杉醇治疗后存活的乳腺癌细胞表达相对高水平的ROR 1，其可以诱导响应Wnt 5a的干细胞信号通路的激活。人源化抗ROR 1药物cirmtuzumab可以抑制ROR 1依赖性激活这种信号传导，并削弱治疗后乳腺癌细胞转移或重新移植免疫缺陷小鼠的能力。耐受化疗治疗的乳腺癌可以富集癌症干细胞或肿瘤起始细胞，其具有增强的自我更新、肿瘤起始和/或转移的能力。表达I型酪氨酸激酶样孤儿受体ROR 1的乳腺癌细胞也可能具有这些特征。在这里，我们发现ROR 1的表达增加乳腺癌细胞化疗后，这也增强了基因的表达诱导激活Rho-GTP酶，Hippo-YAP/TAZ，或B淋巴瘤Mo-MLV插入区1同源物（BMI 1）。ROR 1的表达还增强了乳腺癌细胞侵入基质胶、形成球状体、植入Rag 2 −/−γc−/−小鼠或在紫杉醇治疗后存活的能力。用人源化抗ROR 1单克隆抗体cirmtuzumab治疗携带乳腺癌患者来源的异种移植物（PDX）的小鼠，抑制了与乳腺癌干细胞相关的基因表达，降低了Rho-GTP酶、Hippo-YAP/TAZ或BMI 1的活化，并削弱了乳腺癌PDX转移或再移植Rag 2 −/−γc−/−小鼠的能力。最后，在根除乳腺癌PDX方面，用cirmtuzumab和紫杉醇治疗携带PDX的小鼠比单独治疗更有效。这些结果表明，靶向ROR 1可以改善乳腺癌患者对化疗的反应。
Significance We report that breast cancer cells surviving treatment with paclitaxel express relatively high levels of ROR1, which can induce activation of stem-cell signaling pathways in response to Wnt5a. A humanized anti-ROR1 drug, cirmtuzumab, can inhibit ROR1-dependent activation of such signaling and impair the capacity of post-treatment breast cancer cells to metastasize or reengraft immune-deficient mice. Breast cancers enduring treatment with chemotherapy may be enriched for cancer stem cells or tumor-initiating cells, which have an enhanced capacity for self-renewal, tumor initiation, and/or metastasis. Breast cancer cells that express the type I tyrosine kinaselike orphan receptor ROR1 also may have such features. Here we find that the expression of ROR1 increased in breast cancer cells following treatment with chemotherapy, which also enhanced expression of genes induced by the activation of Rho-GTPases, Hippo-YAP/TAZ, or B lymphoma Mo-MLV insertion region 1 homolog (BMI1). Expression of ROR1 also enhanced the capacity of breast cancer cells to invade Matrigel, form spheroids, engraft in Rag2−/−γc−/− mice, or survive treatment with paclitaxel. Treatment of mice bearing breast cancer patient-derived xenografts (PDXs) with the humanized anti-ROR1 monoclonal antibody cirmtuzumab repressed expression of genes associated with breast cancer stemness, reduced activation of Rho-GTPases, Hippo-YAP/TAZ, or BMI1, and impaired the capacity of breast cancer PDXs to metastasize or reengraft Rag2−/−γc−/− mice. Finally, treatment of PDX-bearing mice with cirmtuzumab and paclitaxel was more effective than treatment with either alone in eradicating breast cancer PDXs. These results indicate that targeting ROR1 may improve the response to chemotherapy of patients with breast cancer.