Mitochondrial Determinants of Chemotherapy Responses in Cancer Cells

参与被称为凋亡的细胞死亡途径对于许多抗癌药物的成功至关重要，无论是新的靶向药物还是传统的细胞毒性药物。无论化疗是传统的细胞毒性化疗，还是更现代的靶向治疗，通常情况下，虽然已知初始靶标，但将其连接到固有凋亡途径的靶标下游信号却知之甚少。因此，化疗敏感性和耐药性的关键分子决定因素在很大程度上是未知的。结果是，我们在预测化疗对哪些肿瘤有反应以及为什么有反应方面做得很差。因此，许多患者暴露在有毒药物中而没有很好的反应机会。在这里，我们提出了一种系统的方法，将药物与上游靶标的接触与线粒体的程序性细胞死亡联系起来。由于BCL-2家族蛋白是关键的调节因子

Engaging the cell death pathway known as apoptosis is critical for the success of many anti-cancer agents, both novel targeted agents and conventional cytotoxic agents. Whether the chemotherapy is conventional cytotoxic chemotherapy, or more modern targeted therapy, it is usually the case that while the initial target is known, the signaling downstream ofthe target that connects it to the intrinsic apoptotic pathway is poorly understood. Therefore, key molecular determinants of sensitivity and resistance to chemotherapy are largely unknown. The consequence, is that we are very bad at predicting what tumors respond to chemotherapy and why. Thus, many patients are exposed to toxic drugs without a good chance at response. Here we propose a systematic approach to connecting the contact of drug to upstream target to the commitment to programmed cell death at the mitochondrion. Since the BCL-2 family of proteins are the key regulators of mitochondrial apoptosis, they will be studied in particular detail. Our goals are to identify complete signaling pathways that are invoked when tumors are killed by anti-mitotic agents or ABT-737. We will use this information to generate predictive models that can predict sensitivity to treatment based solely on certain defined initial conditions. Once these predictive models are validated in in vitro models, we will apply to clinical testing. Furthermore, understanding the signaling pathways that permit successful killing by taxanes may permit the identification of targets in the pathway that can be selectively exploited by less toxic agents. The techniques we will use will include siRNA screening for genes that are essential for priming the apoptotic pathway. In addition, we have developed a new strategy which we call FACS-based BH3 profiling, that allows us to observe, at the single cell level, a cell's death signaling during progression to mitochondrial apoptosis. This strategy will permit a more detailed analysis ofthe role ofthe cell cycle and the role of individual molecules in determining death after treatment with anti-mitotic agents.