Src and STAT3 inhibitors synergize to promote tumor inhibition in renal cell carcinoma.
Src and STAT3 inhibitors synergize to promote tumor inhibition in renal cell carcinoma.
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DOI：
10.18632/oncotarget.5971
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发表时间：
2015-12-29
期刊：
影响因子：
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通讯作者：
Thomas GV
中科院分区：
文献类型：
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作者：
Lue HW;Cole B;Rao SA;Podolak J;Van Gaest A;King C;Eide CA;Wilmot B;Xue C;Spellman PT;Heiser LM;Tyner JW;Thomas GV
胞质内酪氨酸激酶Src作为一个管道和调节器的增殖和生存癌细胞所需的多个过程。在一些癌症中，Src与受体酪氨酸激酶结合以介导下游信号传导，并且在其他癌症中，它调节基因表达。因此，Src代表了一个可行的肿瘤学靶点。然而，迄今为止，对Src抑制剂如达沙替尼的临床反应令人失望。我们确定Stat 3信号传导作为一种潜在的旁路机制，使肾细胞癌（RCC）细胞逃避达沙替尼治疗。使用达沙替尼和CYT 387（JAK/STAT抑制剂）的组合Src-Stat 3抑制协同降低RCC细胞中的细胞增殖并增加细胞凋亡。此外，达沙替尼和CYT 387联合收割机可抑制YAP 1，YAP 1是一种促进细胞增殖、存活和器官大小的转录辅激活因子。重要的是，该组合耐受性良好，并在RCC异种移植物中引起显著的肿瘤抑制。这些结果表明，与Stat 3信号传导抑制剂的联合治疗可能是一种有用的治疗方法，以增加Src抑制剂的疗效。
The intracytoplasmic tyrosine kinase Src serves both as a conduit and a regulator for multiple processes required for the proliferation and survival cancer cells. In some cancers, Src engages with receptor tyrosine kinases to mediate downstream signaling and in other cancers, it regulates gene expression. Src therefore represents a viable oncologic target. However, clinical responses to Src inhibitors, such as dasatinib have been disappointing to date. We identified Stat3 signaling as a potential bypass mechanism that enables renal cell carcinoma (RCC) cells to escape dasatinib treatment. Combined Src-Stat3 inhibition using dasatinib and CYT387 (a JAK/STAT inhibitor) synergistically reduced cell proliferation and increased apoptosis in RCC cells. Moreover, dasatinib and CYT387 combine to suppress YAP1, a transcriptional co-activator that promotes cell proliferation, survival and organ size. Importantly, this combination was well tolerated, and caused marked tumor inhibition in RCC xenografts. These results suggest that combination therapy with inhibitors of Stat3 signaling may be a useful therapeutic approach to increase the efficacy of Src inhibitors.