Wragg Joseph W, Heath Victoria L, Bicknell Roy
Institutes of Cardiovascular Sciences and Biomedical Research, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
Cancer Res. 2017 Feb 15;77(4):1008-1020. doi: 10.1158/0008-5472.CAN-16-1982. Epub 2016 Dec 23.
Antiangiogenic therapies have failed to confer survival benefits in patients with metastatic breast cancer (mBC). However, to date, there has not been an inquiry into the roles for acquired versus innate drug resistance in this setting. In this study, we report roles for these distinct phenotypes in determining therapeutic response in a murine model of mBC resistance to the antiangiogenic tyrosine kinase inhibitor sunitinib. Using tumor measurement and vascular patterning approaches, we differentiated tumors displaying innate versus acquired resistance. Bioluminescent imaging of tumor metastases to the liver, lungs, and spleen revealed that sunitinib administration enhances metastasis, but only in tumors displaying innate resistance to therapy. Transcriptomic analysis of tumors displaying acquired versus innate resistance allowed the identification of specific biomarkers, many of which have a role in angiogenesis. In particular, aquaporin-1 upregulation occurred in acquired resistance, mTOR in innate resistance, and pleiotrophin in both settings, suggesting their utility as candidate diagnostics to predict drug response or to design tactics to circumvent resistance. Our results unravel specific features of antiangiogenic resistance, with potential therapeutic implications. .
抗血管生成疗法未能给转移性乳腺癌（mBC）患者带来生存益处。然而，迄今为止，尚未有人探究在这种情况下获得性耐药与先天性耐药所起的作用。在本研究中，我们报告了这些不同表型在mBC对抗血管生成酪氨酸激酶抑制剂舒尼替尼耐药的小鼠模型中决定治疗反应方面所起的作用。通过肿瘤测量和血管成像方法，我们区分了表现出先天性耐药与获得性耐药的肿瘤。对肝脏、肺和脾脏的肿瘤转移进行生物发光成像显示，给予舒尼替尼会促进转移，但仅在对治疗表现出先天性耐药的肿瘤中如此。对表现出获得性耐药与先天性耐药的肿瘤进行转录组分析，从而确定了特定的生物标志物，其中许多在血管生成中起作用。特别是，水通道蛋白-1上调出现在获得性耐药中，mTOR出现在先天性耐药中，多效生长因子在两种情况下均有出现，这表明它们可作为预测药物反应或设计规避耐药策略的候选诊断标志物。我们的结果揭示了抗血管生成耐药的具体特征，具有潜在的治疗意义。
