Department of Pharmacology, University of Colorado School of Medicine, Aurora, Colorado 80045, USA.
Cancer Res. 2011 Mar 1;71(5):1883-92. doi: 10.1158/0008-5472.CAN-10-2252.
One impediment to the use of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-targeted agents as antitumor drugs is the evolution of resistance, a common problem in cancer. On the contrary, 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 and then comparing them to the TRAIL-sensitive parental cell line. Although diverse classes of anticancer drugs 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 overcome resistance as well as synergize.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）受体靶向药物作为抗肿瘤药物的使用存在一个障碍，即耐药性的出现，这是癌症中的一个常见问题。相反，许多不同类型的药物在 TRAIL 敏感肿瘤细胞中与 TRAIL 协同作用，这就提出了一个问题，即是否可以用产生协同作用的相同药物来克服耐药性。这是一个重要的问题，因为最近的临床试验表明，与单独使用细胞毒性药物相比，联合使用细胞毒性药物和 TRAIL 受体靶向药物并不能为患者带来额外的益处。如果在没有选择保留 TRAIL 敏感性的肿瘤患者中使用协同作用敏感肿瘤细胞但不能克服 TRAIL 耐药性的药物组合，就可能会出现这种结果。我们通过创建获得 TRAIL 耐药性的同源肿瘤细胞或发生在人类肿瘤中的明确耐药机制，并将其与 TRAIL 敏感的亲本细胞系进行比较，来验证这一想法。尽管不同类别的抗癌药物在敏感细胞中均能与 TRAIL 协同作用，但大多数药物不能克服耐药性，而且特定药物与协同作用的量之间没有关系，也不能克服获得性耐药性。一个重要的例外是蛋白酶体抑制剂，它能够克服多种耐药机制。我们的研究结果表明，在选择用于 TRAIL 受体激动剂联合治疗的药物时，不仅应基于其协同作用的能力，还应基于其克服耐药性和协同作用的能力。
