Inhibition of Src Family Kinases and Receptor Tyrosine Kinases by Dasatinib: Possible Combinations in Solid Tumors
Inhibition of Src Family Kinases and Receptor Tyrosine Kinases by Dasatinib: Possible Combinations in Solid Tumors
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DOI：
10.1158/1078-0432.ccr-10-2616
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发表时间：
2011-09-01
影响因子：
11.5
通讯作者：
Pandiella, Atanasio
中科院分区：
文献类型：
--
作者：
Carlos Montero, Juan;Seoane, Samuel;Pandiella, Atanasio
达沙替尼是一种小分子酪氨酸激酶抑制剂，靶向多种与多种肿瘤病理生理学有关的酪氨酸激酶。最敏感的达沙替尼靶点包括ABL、SRC家族激酶（SRC、LCK、HCK、FYN、YES、FGR、BLK、林恩和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（DDR 1）、c-FMS和肝配蛋白受体。达沙替尼抑制细胞复制、迁移和侵袭，并引发肿瘤细胞凋亡。因此，达沙替尼可减少肿瘤质量并减少肿瘤细胞的转移性播散。达沙替尼还作用于肿瘤微环境，这在骨中特别重要，其中达沙替尼抑制骨细胞活性并促进骨生成，发挥骨保护作用。几项临床前研究表明，达沙替尼增强了肿瘤临床中使用的各种药物的抗肿瘤作用，为启动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。使用达沙替尼与ErbB/HER受体拮抗剂组合的试验正在乳腺癌、头颈癌和结直肠癌中进行探索。在激素受体阳性乳腺癌中，使用达沙替尼与抗激素治疗组合的试验正在进行中。达沙替尼联合化疗药物也在开发中，用于治疗前列腺癌（达沙替尼+多西他赛）、黑色素瘤（达沙替尼+达卡巴嗪）和结直肠癌（达沙替尼+奥沙利铂+卡培他滨）。在这里，我们回顾了支持使用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。临床癌症研究; 17（17）; 5546-52。(C)2011年AACR。
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) alpha and beta, 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. Clin Cancer Res; 17(17); 5546-52. (C) 2011 AACR.