Distinct TRAIL resistance mechanisms can be overcome by proteasome inhibition but not generally by synergizing agents.
Distinct TRAIL resistance mechanisms can be overcome by proteasome inhibition but not generally by synergizing agents.
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DOI：
10.1158/0008-5472.can-10-2252
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发表时间：
2011-03-01
期刊：
影响因子：
11.2
通讯作者：
Thorburn A
中科院分区：
文献类型：
--
作者：
Menke C;Bin L;Thorburn J;Behbakht K;Ford HL;Thorburn A
使用TRAIL受体靶向剂作为抗肿瘤药物的一个障碍是耐药性的演变，这是癌症中的常见问题。另一方面，许多不同种类的药物在TRAIL敏感的肿瘤细胞中与TRAIL协同作用，这提出了一个问题，即是否可以用产生协同作用的相同药物克服耐药性。这是一个重要的问题，因为最近的临床试验表明，与细胞毒性药物本身相比，细胞毒性药物和TRAIL受体靶向药物的联合治疗不会提供额外的益处。如果在敏感肿瘤细胞中协同作用但不能克服TRAIL抗性的药物组合用于其肿瘤未被选择用于保留TRAIL敏感性的患者，则可以预期这样的结果。我们通过创建具有获得性TRAIL抗性或在人类肿瘤中发生的定义的抗性机制的同基因肿瘤细胞，然后将它们与TRAIL敏感的亲本细胞系进行比较来测试这一想法。虽然不同类别的抗癌药物都能够与敏感细胞中的TRAIL协同作用，但大多数药物都无法克服耐药性，并且与特定药物的协同作用量与其克服获得性耐药性的能力之间没有关系。一个重要的例外是蛋白酶体抑制剂，但能够克服不同的耐药机制。我们的研究结果表明，人们应该选择药物的TRAIL受体激动剂联合治疗的基础上，不仅是他们的能力，协同作用，而是在他们的能力，克服阻力以及协同作用。
One impediment to the use of TRAIL receptor targeted agents as anti-tumor drugs is the evolution of resistance, a common problem in cancer. On the other hand, many different kinds of drugs synergize with TRAIL in TRAIL-sensitive tumor cells, raising the question whether one can overcome resistance with the same drugs producing synergy. This is an important question, because recent clinical trials suggest that combination treatments with cytotoxic drugs and TRAIL receptor-targeted agents do not provide additional benefit compared with cytotoxic agents on their own. Such results might be expected if drug combinations that synergize in sensitive tumor cells but cannot overcome TRAIL resistance are used in patients whose tumors were not selected for retention of TRAIL sensitivity. We tested this idea by creating isogenic tumor cells with acquired TRAIL resistance or defined mechanisms of resistance that occur in human tumors then compared them to the TRAIL-sensitive parental cell line. Although diverse classes of anti-cancer drug were all able to synergize with TRAIL in sensitive cells, most agents were unable to overcome resistance and there was no relationship between the amount of synergy seen with a particular agent and its ability to overcome acquired resistance. An important exception was proteasome inhibitors, which were however able to overcome diverse resistance mechanisms. Our findings suggest that one should select drugs for TRAIL receptor agonist combination therapy based not just on their ability to synergize but rather on their ability to both overcome resistance as well as synergize.