Faivre Sandrine, Djelloul Siham, Raymond Eric
Department of Medical Oncology, Hŏpital Beaujon, Clichy Cedex, Clichy, France.
Semin Oncol. 2006 Aug;33(4):407-20. doi: 10.1053/j.seminoncol.2006.04.005.
Signal transduction in cancer cells is a sophisticated process that involves receptor tyrosine kinases (RTKs) that eventually trigger multiple cytoplasmic kinases, which are often serine/threonine kinases. A number of tumor models have identified several key cellular signaling pathways that work independently, in parallel, and/or through interconnections to promote cancer development. Three major signaling pathways that have been identified as playing important roles in cancer include the phosphatidyl inositol-3-kinase (PI3K)/AKT, protein kinase C (PKC) family, and mitogen-activated protein kinase (MAPK)/Ras signaling cascades. In clinical trials, highly selective or specific blocking of only one of the kinases involved in these signaling pathways has been associated with limited or sporadic responses. Improved understanding of the complexity of signal transduction processes and their roles in cancer has suggested that simultaneous inhibition of several key kinases at the level of receptors and/or downstream serine/threonine kinases may help to optimize the overall therapeutic benefit associated with molecularly targeted anticancer agents. Using targeted agents to inhibit multiple signaling pathways has emerged as a new paradigm for anticancer treatment based on preclinical and clinical data showing potent anti-tumor activity of single drugs inhibiting multiple molecular targets or combination therapies involving multiple drugs with selective or narrow target specificity. Preclinical and clinical studies point to molecules on vascular endothelial cells and pericytes as being important targets for anticancer therapies, as well as molecules on or within tumor cells themselves. This suggests that optimal therapeutic approaches to cancer may involve targeting multiple molecules found in both the tumor and supportive tissues. In this review, we will use the most recent preclinical and clinical data to describe this emerging paradigm for anticancer therapy involving targeting multiple signaling pathways with tyrosine or serine/threonine kinase inhibitors.
癌细胞中的信号转导是一个复杂的过程，涉及受体酪氨酸激酶（RTK），其最终会触发多种细胞质激酶，这些激酶通常是丝氨酸/苏氨酸激酶。许多肿瘤模型已经确定了几个关键的细胞信号通路，它们独立、并行和/或通过相互连接发挥作用，以促进癌症发展。已确定在癌症中起重要作用的三个主要信号通路包括磷脂酰肌醇-3-激酶（PI3K）/AKT、蛋白激酶C（PKC）家族和丝裂原活化蛋白激酶（MAPK）/Ras信号级联。在临床试验中，仅对这些信号通路中涉及的一种激酶进行高度选择性或特异性阻断，其反应有限或零星。对信号转导过程的复杂性及其在癌症中的作用的进一步了解表明，在受体水平和/或下游丝氨酸/苏氨酸激酶水平同时抑制几种关键激酶，可能有助于优化与分子靶向抗癌药物相关的整体治疗效果。基于临床前和临床数据显示，单一药物抑制多个分子靶点或多种具有选择性或窄靶点特异性的药物联合治疗具有强大的抗肿瘤活性，使用靶向药物抑制多个信号通路已成为抗癌治疗的新范式。临床前和临床研究指出，血管内皮细胞和周细胞上的分子以及肿瘤细胞本身表面或内部的分子是抗癌治疗的重要靶点。这表明，最佳的癌症治疗方法可能涉及靶向肿瘤和支持组织中发现的多种分子。在本综述中，我们将使用最新的临床前和临床数据来描述这种涉及用酪氨酸或丝氨酸/苏氨酸激酶抑制剂靶向多个信号通路的抗癌治疗新范式。
