肺癌细胞自我毁灭诱导成功 有望开发肺癌靶向疗法

  近日，在美国国家癌症研究所利物浦癌症会议上，癌症专家表示他们发现了一种药物组合可以诱发肺癌细胞自我毁灭，从而为开发治疗肺癌的新型疗法提供了一定的思路。
  当健康细胞不再有用时其就会启动一系列事件进行自我毁灭，但是癌细胞往往会脱离这种自杀路径变成永生细胞，这就意味着失去控制的细胞就会引发肿瘤的形成，而最新研究中研究人员成功地揭示了肺癌细胞的永生之谜，而且通过重编程肺癌细胞就可以促进其自我毁灭。利用肺癌细胞和小鼠模型进行研究，科学家揭示了，两种药物：TRAIL和CDK9抑制剂的联合使用可改变细胞自杀过程的分子开关，从而驱动癌细胞进行自我毁灭。
  Henning Walczak教授说道，“点燃”促进肺癌细胞自我毁灭的导火索或许就为我们开发彻底治愈肺癌的新型疗法提供帮助。下一步我们想去观察如何在其它类型癌症中实现癌细胞的自我毁灭，研究者希望这种新型药物联合的疗法可以帮助更多患者脱离癌症的困扰。
  揭示癌细胞永生之谜对开发有效抑制癌细胞无限增殖的新型疗法非常关键，也为人们战胜癌症病魔提供了新的希望，当前临床上迫切需要治疗肺癌的疗法，因此研究人员希望本文的研究或为开发治疗肺癌的新型疗法提供新的理论依据和希望。（转化医学网360zhyx.com）
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Selective CDK9 inhibition overcomes TRAIL resistance in NSCLC
2014 NCRI Cancer Conference
Antonella Montinaro1, Johannes Lemke1, Silvia von Karstedt1, Henning Walczak1
Background
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in cancer cells without causing toxicity in vivo. However, to date TRAIL-receptor agonists have shown only limited therapeutic benefit in clinical trials. This can, most likely, be attributed to the fact that most primary human cancers are TRAIL-resistant. Hence, future TRAIL-based therapies will require the addition of sensitizing agents that remove crucial blocks in the TRAIL apoptosis pathway.
Method
PIK-75 strongly sensitises cancer cells to TRAIL-induced apoptosis independently of inhibition of p110?. We performed a kinome-wide screen to identify which kinases were inhibited by PIK-75. To evaluate which of the 27 kinases inhibited was responsible for PIK-75-mediated sensitization to TRAIL-induced apoptosis, we screened all 27 kinases identified by siRNA knockdown. We next assessed the potency of SNS-032 (the clinically used inhibitor of CDK9) and TRAIL combination in vitro in a panel of NSCLC cell lines and in vivo using an orthotopic model of lung cancer.
Results
We identified CDK9, a PIK-75-target, to be responsible for TRAIL resistance of cancer cells. The combination of CDK9 inhibition with TRAIL effectively induced apoptosis even in highly TRAIL-resistant cancer cells. Mechanistically, CDK9 inhibition resulted in the downregulation of cFlip and Mcl-1, at both the mRNA and protein levels. Furthermore, we found that a panel of mostly TRAIL-resistant NSCLC cell lines was readily killed by the combination of TRAIL and SNS-032, even at low concentrations of TRAIL. Importantly, primary human hepatocytes did not succumb to the same treatment regime, defining a therapeutic window for the combination of TRAIL with CDK9 inhibitors. Importantly, the combination of SNS-032 and TRAIL was also highly effective in vivo and led to eradication of established orthotopic NSCLC tumors.
Conclusion
Based on the high potency of CDK9 inhibition as a cancer cell-selective TRAIL-sensitizing strategy, we envisage the development of new, highly effective cancer therapies.