Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medicine (Hematology/Oncology), Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
PLoS One. 2013 Sep 26;8(9):e75414. doi: 10.1371/journal.pone.0075414. eCollection 2013.
Approximately half of tumor cell lines are resistant to the tumor-selective apoptotic effects of tumor necrosis factor-related apoptosis-inducing ligand (Apo22L/TRAIL). Previously, we showed that combining Apo2L/TRAIL with sorafenib, a multikinase inhibitor, results in dramatic efficacy in Apo2L/TRAIL-resistant tumor xenografts via inhibition of Mcl-1. Soluble Apo2L/TRAIL is capable of binding to several surface receptors, including the pro-apoptotic death receptors, DR4 and DR5, and decoy receptors, DcR1 and DcR2. Monoclonal antibodies targeting either of these death receptors are being investigated as antitumor agents in clinical trials. We hypothesized that sorafenib and Apo2L/TRAIL or Apo2L/TRAIL death receptor agonist (TRA) antibodies against DR4 (mapatumumab) and DR5 (lexatumumab) will overcome resistance to Apo2L/TRAIL-mediated apoptosis and as increase antitumor efficacy in Apo2L/TRAIL-sensitive solid tumors.
METHODOLOGY/PRINCIPAL FINDINGS: We found that Apo2L/TRAIL or TRA antibodies combined with sorafenib synergistically reduce cell growth and increase cell death across a panel of solid tumor cell lines in vitro. This panel included human breast, prostate, colon, liver and thyroid cancers. The cooperativity of these combinations was also observed in vivo, as measured by tumor volume and TUNEL staining as a measure of apoptosis. We found that sorafenib inhibits Jak/Stat3 signaling and downregulates their target genes, including cyclin D1, cyclin D2 and Mcl-1, in a dose-dependent manner.
CONCLUSIONS/SIGNIFICANCE: The combination of sorafenib with Apo2L/TRAIL or Apo2L/TRAIL receptor agonist antibodies sensitizes Apo2L/TRAIL-resistant cells and increases the sensitivity of Apo2L/TRAIL-sensitive cells. Our findings demonstrate the involvement of the Jak2-Stat3-Mcl1 axis in response to sorafenib treatment, which may play a key role in sorafenib-mediated sensitization to Apo2L/TRAIL.
约有一半的肿瘤细胞系对肿瘤坏死因子相关凋亡诱导配体（Apo22L/TRAIL）的肿瘤选择性凋亡作用具有抗性。以前，我们表明，通过抑制 Mcl-1，将 Apo2L/TRAIL 与多激酶抑制剂索拉非尼联合使用，可显著提高 Apo2L/TRAIL 耐药肿瘤异种移植物的疗效。可溶性 Apo2L/TRAIL 能够与几种表面受体结合，包括促凋亡的死亡受体 DR4 和 DR5，以及诱饵受体 DcR1 和 DcR2。针对这些死亡受体中的任何一种的单克隆抗体都被作为抗肿瘤药物在临床试验中进行研究。我们假设索拉非尼和 Apo2L/TRAIL 或 Apo2L/TRAIL 死亡受体激动剂（TRA）抗体针对 DR4（mapatumumab）和 DR5（lexatumumab）将克服对 Apo2L/TRAIL 介导的细胞凋亡的抗性，并增加 Apo2L/TRAIL 敏感的实体肿瘤的抗肿瘤疗效。
方法/主要发现：我们发现 Apo2L/TRAIL 或 TRA 抗体与索拉非尼联合使用可在体外协同减少一系列实体肿瘤细胞系的细胞生长并增加细胞死亡。该面板包括人乳腺癌、前列腺癌、结肠癌、肝癌和甲状腺癌。这些组合的协同作用也在体内观察到，通过肿瘤体积和 TUNEL 染色作为凋亡的测量来衡量。我们发现索拉非尼以剂量依赖性方式抑制 Jak/Stat3 信号传导并下调其靶基因，包括细胞周期蛋白 D1、细胞周期蛋白 D2 和 Mcl-1。
结论/意义：索拉非尼与 Apo2L/TRAIL 或 Apo2L/TRAIL 受体激动剂抗体的联合使用使 Apo2L/TRAIL 耐药细胞敏感，并增加了 Apo2L/TRAIL 敏感细胞的敏感性。我们的研究结果表明，Jak2-Stat3-Mcl1 轴参与了对索拉非尼治疗的反应，这可能在索拉非尼介导的对 Apo2L/TRAIL 的增敏作用中发挥关键作用。
