Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA 90095, USA.
Neoplasia. 2010 Aug;12(8):599-607. doi: 10.1593/neo.10328.
The SRC family kinases are the largest family of nonreceptor tyrosine kinases and one of the best-studied targets for cancer therapy. SRC, arguably the oldest oncogene, has been implicated in pathways regulating proliferation, angiogenesis, invasion and metastasis, and bone metabolism. More recently, researchers have proposed that the transforming ability of SRC is linked to its ability to activate key signaling molecules in these pathways, rather than through direct activity. It has been hypothesized that blocking SRC activation may inhibit these pathways, resulting in antitumor activity. However, successfully targeting SRC in a clinical setting remains a challenge, and SRC inhibitors have only recently begun to move through clinical development. Preclinical studies have identified specific molecular "subgroups" and histologies that may be more sensitive to SRC inhibition. In addition, other studies have demonstrated synergistic interactions between SRC inhibitors and other targeted therapies and cytotoxics. In this review, we summarize SRC biology and how it has been applied to the clinical development of SRC inhibitors. The status of SRC inhibitors, including dasatinib, saracatinib, and bosutinib, which are in phase 1, 2, and 3 trials, is highlighted.
Src 家族激酶是最大的非受体酪氨酸激酶家族之一，也是癌症治疗研究最深入的靶点之一。Src 可以说是最古老的癌基因，它参与了调节增殖、血管生成、侵袭和转移以及骨代谢的途径。最近，研究人员提出，Src 的转化能力与其激活这些途径中的关键信号分子的能力有关，而不是通过直接活性。有人假设阻断 SRC 的激活可能会抑制这些途径，从而产生抗肿瘤活性。然而，在临床环境中成功靶向 SRC 仍然是一个挑战，并且 SRC 抑制剂最近才开始进入临床开发阶段。临床前研究已经确定了特定的分子“亚群”和组织学可能对 SRC 抑制更敏感。此外，其他研究表明 SRC 抑制剂与其他靶向治疗药物和细胞毒素之间存在协同作用。在这篇综述中，我们总结了 Src 的生物学特性及其在 SRC 抑制剂的临床开发中的应用。强调了处于 1 期、2 期和 3 期临床试验中的 dasatinib、saracatinib 和 bosutinib 等 SRC 抑制剂的现状。
