Finn R S
Department of Medicine, Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
Ann Oncol. 2008 Aug;19(8):1379-1386. doi: 10.1093/annonc/mdn291. Epub 2008 May 16.
The clinical benefit of blocking oncogenic pathways in breast cancer and other malignancies has validated this approach and ushered in the era of molecularly targeted therapeutics. Src and its family members make up the largest group of nonreceptor tyrosine kinases. In laboratory models, these proteins have been shown to play a critical role in cellular growth and proliferation, angiogenesis, and invasion and metastasis. In addition, Src plays an important role in osteoclast activation and bone resorption, which are often aberrantly activated in the setting of bone metastases. Given its role in these functions, blocking Src kinase would be predicted to have a broad therapeutic benefit in patients with Src-dependent cancers. In this review, we highlight the rationale for targeting Src in breast cancer, including laboratory and clinical data implicating it in these signaling pathways, and review small-molecule tyrosine kinase inhibitors currently in clinical development. Identifying which patients should be selected for Src-directed therapies will be important to the clinical success of these agents. Importantly, recent preclinical data support a role for this class of inhibitors in basal-type/triple-negative breast cancer, which represents a group of patients with limited effective treatment options.
在乳腺癌和其他恶性肿瘤中阻断致癌途径的临床益处证实了这种方法，并开启了分子靶向治疗的时代。Src及其家族成员构成了最大的非受体酪氨酸激酶组。在实验室模型中，这些蛋白质已被证明在细胞生长和增殖、血管生成以及侵袭和转移中起关键作用。此外，Src在破骨细胞活化和骨吸收中起重要作用，而在骨转移情况下这些过程常常异常激活。鉴于其在这些功能中的作用，预计阻断Src激酶对Src依赖性癌症患者具有广泛的治疗益处。在本综述中，我们强调了在乳腺癌中靶向Src的基本原理，包括将其牵涉到这些信号通路中的实验室和临床数据，并综述了目前处于临床开发阶段的小分子酪氨酸激酶抑制剂。确定哪些患者应被选用于Src导向治疗对于这些药物的临床成功至关重要。重要的是，最近的临床前数据支持这类抑制剂在基底型/三阴性乳腺癌中的作用，这代表了一组有效治疗选择有限的患者。
