Instituto de Biología Molecular y Celular del Cáncer-Centro de Investigación del Cáncer (CIC), Consejo Superior de Investigaciones Cientificas (CSIC)-Universidad de Salamanca, Salamanca, Spain.
Clin Cancer Res. 2011 Sep 1;17(17):5546-52. doi: 10.1158/1078-0432.CCR-10-2616. Epub 2011 Jun 13.
Dasatinib is a small molecule tyrosine kinase inhibitor that targets a wide variety of tyrosine kinases implicated in the pathophysiology of several neoplasias. Among the most sensitive dasatinib targets are ABL, the SRC family kinases (SRC, LCK, HCK, FYN, YES, FGR, BLK, LYN, and FRK), and the receptor tyrosine kinases c-KIT, platelet-derived growth factor receptor (PDGFR) α and β, discoidin domain receptor 1 (DDR1), c-FMS, and ephrin receptors. Dasatinib inhibits cell duplication, migration, and invasion, and it triggers apoptosis of tumoral cells. As a consequence, dasatinib reduces tumoral mass and decreases the metastatic dissemination of tumoral cells. Dasatinib also acts on the tumoral microenvironment, which is particularly important in the bone, where dasatinib inhibits osteoclastic activity and favors osteogenesis, exerting a bone-protecting effect. Several preclinical studies have shown that dasatinib potentiates the antitumoral action of various drugs used in the oncology clinic, paving the way for the initiation of clinical trials of dasatinib in combination with standard-of-care treatments for the therapy of various neoplasias. Trials using combinations of dasatinib with ErbB/HER receptor antagonists are being explored in breast, head and neck, and colorectal cancers. In hormone receptor-positive breast cancer, trials using combinations of dasatinib with antihormonal therapies are ongoing. Dasatinib combinations with chemotherapeutic agents are also under development in prostate cancer (dasatinib plus docetaxel), melanoma (dasatinib plus dacarbazine), and colorectal cancer (dasatinib plus oxaliplatin plus capecitabine). Here, we review the preclinical evidence that supports the use of dasatinib in combination for the treatment of solid tumors and describe various clinical trials developed following a preclinical rationale.
达沙替尼是一种小分子酪氨酸激酶抑制剂，可靶向多种酪氨酸激酶，这些激酶与多种肿瘤的病理生理学有关。达沙替尼最敏感的靶点包括 ABL、SRC 家族激酶（SRC、LCK、HCK、FYN、YES、FGR、BLK、LYN 和 FRK）以及受体酪氨酸激酶 c-KIT、血小板衍生生长因子受体（PDGFR）α和β、盘状结构域受体 1（DDR1）、c-FMS 和 Eph 受体。达沙替尼抑制细胞复制、迁移和侵袭，并触发肿瘤细胞凋亡。因此，达沙替尼可降低肿瘤体积并减少肿瘤细胞的转移扩散。达沙替尼还作用于肿瘤微环境，这在骨骼中尤为重要，因为达沙替尼可抑制破骨细胞活性并促进成骨作用，发挥骨保护作用。多项临床前研究表明，达沙替尼增强了临床肿瘤学中各种药物的抗肿瘤作用，为开展达沙替尼与标准治疗联合治疗各种肿瘤的临床试验铺平了道路。正在探索用达沙替尼联合 ErbB/HER 受体拮抗剂治疗乳腺癌、头颈部癌和结直肠癌的临床试验。在激素受体阳性乳腺癌中，正在进行用达沙替尼联合抗激素治疗的临床试验。用达沙替尼联合化疗药物治疗前列腺癌（达沙替尼加多西他赛）、黑色素瘤（达沙替尼加达卡巴嗪）和结直肠癌（达沙替尼加奥沙利铂加卡培他滨）的临床试验也在进行中。在这里，我们综述了支持达沙替尼联合治疗实体瘤的临床前证据，并描述了根据临床前原理开发的各种临床试验。
