Imatinib upregulates compensatory integrin signaling in a mouse model of gastrointestinal stromal tumor and is more effective when combined with dasatinib.
Imatinib upregulates compensatory integrin signaling in a mouse model of gastrointestinal stromal tumor and is more effective when combined with dasatinib.
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DOI：
10.1158/1541-7786.mcr-10-0065
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发表时间：
2010-09
期刊：
影响因子：
--
通讯作者：
Besmer P
中科院分区：
文献类型：
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作者：
Rossi F;Yozgat Y;de Stanchina E;Veach D;Clarkson B;Manova K;Giancotti FG;Antonescu CR;Besmer P
Kit 受体酪氨酸激酶的激活突变与胃肠道间质瘤 (GIST) 相关。伊马替尼抑制 Kit，是 GIST 的一线治疗药物。然而，伊马替尼通常会引起部分反应或病情稳定，大多数最初对伊马替尼有反应的胃肠道间质瘤患者最终会产生耐药性。因此需要改进 GIST 的治疗策略。我们在人类 GIST 小鼠模型中研究了 Src 家族激酶 (SFK) 在肿瘤发生中的作用。尽管 SFK Src 和 Lyn 在 GIST 中具有活性，但令人惊讶的是伊马替尼治疗刺激了它们的磷酸化/激活。我们发现，整合素信号传导激活 FAK，从而激活 GIST 中的 SFK，伊马替尼增强整合素信号传导意味着细胞外基质和整合素信号传导在肿瘤维持和伊马替尼耐药中发挥作用。达沙替尼是 SFK 和 Kit 的抑制剂，可抑制 GIST 中的 SFK 和 FAK 激活，同时也抑制 Kit 和 Kit 依赖性下游信号通路，包括 PI3 激酶、MAPK，但不抑制 STAT 信号传导。虽然达沙替尼和伊马替尼单独使用都产生最小的组织病理学反应，但联合治疗改善了这种反应，导致胃肠道间质瘤坏死增加。这些结果强调了 SFK 和 STAT 信号传导在 GIST 中的重要性，并表明伊马替尼对整合素信号传导的刺激可能会限制其临床疗效。
Activating mutations in the Kit receptor tyrosine kinase are associated with Gastrointestinal Stromal Tumor (GIST). Imatinib inhibits Kit and is front-line therapy for GIST. However, imatinib most often elicits a partial response or stable disease and most GIST patients who initially respond to imatinib eventually acquire resistance. Thus improved treatment strategies for GIST are needed. We investigated the role of Src Family kinases (SFKs) in tumorigenesis in a mouse model of human GIST. Whereas the SFKs Src and Lyn were active in GIST, surprisingly imatinib treatment stimulated their phosphorylation/activation. We show that integrin signaling activates FAK and consequently SFKs in GIST and that imatinib enhanced integrin signaling implies a role for the extracellular matrix and integrin signaling in tumor maintenance and imatinib resistance. Dasatinib, an inhibitor of SFKs and Kit, inhibited SFKs and FAK activation in GIST but also inhibited Kit and Kit-dependent downstream signaling pathways including PI3-kinase, MAPK but not STAT signaling. While dasatinib and imatinib alone both produced a minimal histo-pathological response, combination therapy improved it leading to increased necrosis in GIST. These results highlight the importance of SFK and STAT signaling in GIST and suggest that stimulation of integrin signaling by imatinib may limit its clinical efficacy.