Drug Discovery Department, Moffitt Cancer Center, Tampa, Florida 33612, USA.
J Cell Physiol. 2012 Sep;227(9):3178-84. doi: 10.1002/jcp.24065.
AKT/PKB serine threonine kinase, a critical signaling molecule promoting cell growth and survival pathways, is frequently dysregulated in many cancers. Although phosphatidylinositol-3-OH kinase (PI3K), a lipid kinase, is well characterized as a major regulator of AKT activation in response to a variety of ligands, recent studies highlight a diverse group of tyrosine (Ack1/TNK2, Src, PTK6) and serine/threonine (TBK1, IKBKE, DNAPKcs) kinases that activate AKT directly to promote its pro-proliferative signaling functions. While some of these alternate AKT activating kinases respond to growth factors, others respond to inflammatory and genotoxic stimuli. A common theme emerging from these studies is that aberrant or hyperactivation of these alternate kinases is often associated with malignancy. Consequently, evaluating the use of small molecular inhibitors against these alternate AKT activating kinases at earlier stages of cancer therapy may overcome the pressing problem of drug resistance surfacing especially in patients treated with PI3K inhibitors.
AKT/PKB 丝氨酸苏氨酸激酶是一种促进细胞生长和存活途径的关键信号分子，在许多癌症中经常失调。虽然磷脂酰肌醇-3-OH 激酶 (PI3K) 作为一种脂质激酶，作为 AKT 激活的主要调节剂而得到很好的描述，以响应各种配体，但最近的研究强调了一组不同的酪氨酸 (Ack1/TNK2、Src、PTK6) 和丝氨酸/苏氨酸 (TBK1、IKBKE、DNAPKcs) 激酶，它们可以直接激活 AKT，以促进其促增殖信号功能。虽然其中一些替代 AKT 激活激酶对生长因子有反应，但其他激酶对炎症和遗传毒性刺激有反应。这些研究中出现的一个共同主题是，这些替代 AKT 激活激酶的异常或过度激活通常与恶性肿瘤有关。因此，在癌症治疗的早期阶段评估针对这些替代 AKT 激活激酶的小分子抑制剂的使用可能会克服药物耐药性出现的紧迫问题，特别是在接受 PI3K 抑制剂治疗的患者中。
