Contribution of individual targets to the antitumor efficacy of the multitargeted receptor tyrosine kinase inhibitor SU11248
Contribution of individual targets to the antitumor efficacy of the multitargeted receptor tyrosine kinase inhibitor SU11248
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DOI：
10.1158/1535-7163.mct-03-0156
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发表时间：
2006-05-01
影响因子：
5.7
通讯作者：
Mendel, Dirk B.
中科院分区：
文献类型：
--
作者：
Potapova, Olga;Laird, A. Douglas;Mendel, Dirk B.
最近在多靶点分子抑制剂的发展中取得的成就需要更好地理解对单个靶点的活性对其功效的贡献。SU 11248是一种靶向III/V类受体酪氨酸激酶（包括血小板衍生生长因子（PIDGF）和血管内皮生长因子（VEGF）受体、KIT和FLT 3）的小分子抑制剂，对癌细胞具有直接作用以及抗血管生成活性。在此，我们研究了在代表不同信号传导模式的肿瘤模型中抑制单个SU 11248靶受体对其总体抗肿瘤疗效的贡献。与之前的结果一致，SU 11248在所有试验模型中均高度有效（通常为细胞减少）。为了阐明抑制PDGF和VEGF受体对SU 11248体内疗效的具体贡献，我们采用了两种选择性抑制剂，SU 10944（VEGF受体抑制剂）和Gleevec（PDGF受体抑制剂）。SU 10944单独在所有评价的模型中诱导肿瘤生长延迟，与主要的抗血管生成作用模式一致。相反，格列卫在肿瘤模型中导致适度的生长抑制，其中癌细胞表达其靶点（PIDGFR β和KIT），但对不是由这些靶受体酪氨酸激酶驱动的肿瘤无效。值得注意的是，在所有评价的肿瘤模型中，除了一个模型外，SU 10944联合Gleevec的抗肿瘤疗效与单药SU 11248相似，并且大大上级每种化合物单独使用，表明SU 11248在这些模型中的抗肿瘤效力源于对PDGF和VEGF受体的联合抑制。一个例外是由FLT 3的活化突变体驱动的模型，其中靶向FLT 3的SU 11248的活性大于SU 10944加格列卫的活性。此外，SU 10944与Gleevec组合抑制肿瘤新生血管生成的程度与SU 11248相当。因此，SU 11248在代表不同信号传导范式的模型中的强效功效是由于同时抑制癌细胞和肿瘤新血管系统中表达的单个靶受体，支持多靶点抑制剂具有组合单靶点抑制剂的累积抗肿瘤功效的假设。
Recent achievements in the development of multitargeted molecular inhibitors necessitate a better understanding of the contribution of activity against individual targets to their efficacy. SU11248, a small-molecule inhibitor targeting class III/V receptor tyrosine kinases, including the platelet-derived growth factor (PIDGF) and vascular endothelial growth factor (VEGF) receptors, KIT and FLT3, exhibits direct effects on cancer cells as well as antiangiogenic activity. Here, we investigated the contributions of inhibiting individual SU 11248 target receptors to its overall antitumor efficacy in tumor models representing diverse signaling paradigms. Consistent with previous results, SU 11248 was highly efficacious (frequently cytoreductive) in all models tested. To elucidate the specific contributions of inhibition of PDGF and VEGF receptors to the in vivo efficacy of SU11248, we employed two selective inhibitors, SU10944 (VEGF receptor inhibitor) and Gleevec (PDGF receptor inhibitor). SU10944 alone induced a tumor growth delay in all models evaluated, consistent with a primarily antiangiogenic mode of action. In contrast, Gleevec resulted in modest growth inhibition in tumor models in which the cancer cells expressed its targets (PIDGFR beta and KIT), but was not efficacious against tumors not driven by these target receptor tyrosine kinases. Strikingly, in all but one tumor model evaluated, the antitumor efficacy of SU10944 combined with Gleevec was similar to that of single-agent SU11248, and was greatly superior to that of each compound alone, indicating that the antitumor potency of SU 11248 in these models stems from combined inhibition of both PDGF and VEGF receptors. The one exception was a model driven by an activated mutant of FLT3, in which the activity of SU11248, which targets FLT3, was greater than that of SU10944 plus Gleevec. Moreover, SU10944 combined with Gleevec inhibited tumor neoangiogenesis to an extent comparable to that of SU11248. Thus, the potent efficacy of SU11248 in models representing diverse signaling paradigms results from simultaneous inhibition of individual target receptors expressed both in cancer cells and in the tumor neovasculature, supporting the hypothesis that multitargeted inhibitors have the cumulative antitumor efficacy of combined single-target inhibitors.