Sorafenib and Quinacrine Target Anti-Apoptotic Protein MCL1: A Poor Prognostic Marker in Anaplastic Thyroid Cancer (ATC).
Sorafenib and Quinacrine Target Anti-Apoptotic Protein MCL1: A Poor Prognostic Marker in Anaplastic Thyroid Cancer (ATC).
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DOI：
10.1158/1078-0432.ccr-15-2792
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发表时间：
2016-12-15
期刊：
影响因子：
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通讯作者：
El-Deiry WS
中科院分区：
文献类型：
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作者：
Abdulghani J;Gokare P;Gallant JN;Dicker D;Whitcomb T;Cooper T;Liao J;Derr J;Liu J;Goldenberg D;Finnberg NK;El-Deiry WS
未分化甲状腺癌（ATC）占所有甲状腺癌的约2%，其中位生存率仍然很低。它是导致超过三分之一的甲状腺癌相关死亡的原因。ATC通常对常规治疗有抵抗力，并且NFκ B信号传导已被认为是该疾病的特征。我们的目的是评估已知靶向NFκ B信号传导的抗疟疾药物奎纳克林与临床相关激酶抑制剂索拉非尼联合在ATC细胞中的活性。通过Meta数据基因集富集分析和免疫组织化学（IHC）证实ATC中存在NFκB-p65/RelA及其靶点Mcl-1。我们评估了一组人ATC细胞系在体外和体内对奎纳克林和索拉非尼的反应。与非肿瘤性甲状腺相比，我们检测到ATC亚群细胞核中NFκB-p65/RelA和Mcl-1的表达增加。发现ATC-细胞在体外对索拉非尼加奎纳克林的组合以相加/协同的肿瘤细胞杀伤应答，并且与单独施用化合物或多柔比星的小鼠相比，药物组合改善了原位注射ATC-细胞的免疫缺陷小鼠的存活。我们还证明索拉非尼和奎纳克林的组合在小鼠中耐受性良好。在分子水平上，奎纳克林和索拉非尼B抑制促存活基因Mcl-1、pStat 3的表达并抑制NFκB信号传导。奎纳克林和索拉非尼的组合靶向ATC的新兴分子标志，并在该疾病的临床相关模型中显示出有希望的结果。可以在ATC患者中进行索拉非尼加奎纳克林的进一步测试。索拉非尼和奎纳克林的药物组合靶向Mcl-1并在难以治疗的间变性甲状腺癌细胞中引发协同反应，从而潜在地提供了用于临床进一步测试的新型治疗组合。
Anaplastic thyroid cancer (ATC) comprises ~2% of all thyroid cancers and its median survival rate remains poor. It is responsible for more than one-third of thyroid cancer-related deaths. ATC is frequently resistant to conventional therapy and NFκB-signaling has been proposed to be a feature of the disease. We aimed to assess the activity of the anti-malaria drug quinacrine known to target NFκB-signaling in combination with the clinically relevant kinase inhibitor sorafenib in ATC cells. The presence of NFκB-p65/RelA and its target Mcl-1 was demonstrated in ATC by meta-data gene set enrichment analysis and immunohistochemistry (IHC). We assessed the responses of a panel of human ATC cell lines to quinacrine and sorafenib in vitro and in vivo. We detected increased expression of NFκB-p65/RelA and Mcl-1 in the nucleus of a subset of ATC compared to non-neoplastic thyroid. ATC-cells were found to respond with additive/synergistic tumor cell-killing to the combination of sorafenib plus quinacrine in vitro and the drug combination improves survival of immunodeficient mice injected orthotopically with ATC-cells as compared to mice administered either compound alone or doxorubicin. We also demonstrate that the combination of sorafenib and quinacrine is well tolerated in mice. At the molecular level, quinacrine and sorafenib inhibited expression of the pro-survival gene Mcl-1, pStat3 and dampened NFκB signaling. The combination of quinacrine and sorafenib targets emerging molecular hallmarks of ATC and shows promising results in clinically relevant models for the disease. Further testing of sorafenib plus quinacrine can be conducted in ATC patients. The drug combination of sorafenib and quinacrine targets Mcl-1 and triggers synergistic responses in difficult to treat anaplastic thyroid cancer cells thereby potentially offering a novel therapy combination for further testing in the clinic.