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首页> 外文期刊>Neoplasia: an international journal for oncology research >IGF-1R Inhibition Activates a YES/SFK Bypass Resistance Pathway: Rational Basis for Co-Targeting IGF-1R and Yes/SFK Kinase in Rhabdomyosarcoma
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IGF-1R Inhibition Activates a YES/SFK Bypass Resistance Pathway: Rational Basis for Co-Targeting IGF-1R and Yes/SFK Kinase in Rhabdomyosarcoma

机译：IGF-1R抑制激活A / SFK旁路电阻途径：在横纹肌肉瘤中共靶向IGF-1R的合理基础，是/ SFK激酶

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The insulin-like growth factor 1 receptor (IGF-1R) has surfaced as a significant target in multiple solid cancers due to its fundamental roles in pro-survival and anti-apoptotic signaling. However, development of resistance to IGF-1R blockade represents a significant hindrance and limits treatment efficacy in the clinic. In this study, we identified acquired resistance to IGF-1R blockade with R1507, an antibody against IGF-1R, and with BMS-754807, a small molecular inhibitor of IGF-1R/insulin receptor (IR). We showed that treatment with an IGF-IR antibody, R1507, or an IR/IGF-IR kinase inhibitor, BMS-754807, was associated with increased activation of YES/SRC family tyrosine kinase (SFK) in rhabdomyosarcoma (RMS). Combining anti–IGF-1R agents with SFK inhibitors resulted in blockade of IGF-1R inhibition–induced activation of YES/SFK and displayed advantageous antitumor activity in vitro and in vivo. Our data provide evidence that IGF-1R blockade results in activation of the YES/SRC family kinase bypass resistance pathway in vitro and in vivo. This may be of particular clinical relevance since both Yes and IGF components are overexpressed in RMS. Increased YES/SFK activation might serve as a clinical biomarker for predicting tumor resistance to IGF-1R inhibition. Dual inhibition of IGF-1R and SFK may have a broader and enhanced clinical benefit for patients with RMS.
机译：由于其基本作用，胰岛素样生长因子1受体（IGF-1R）在多种固体癌症中浮出水面的靶标，这是在促存活和抗凋亡信号传导中的基本作用。然而，对IGF-1R阻断的抗性的发展表示显着的障碍，并限制诊所的治疗效果。在该研究中，我们鉴定了对IGF-1R阻断的抗性对IGF-1R的抗体，并且具有BMS-754807的IGF-1R /胰岛素受体（IR）的小分子抑制剂（IR）。我们表明，用IGF-IR抗体，R1507或IR / IGF-IR激酶BMS-754807的治疗与横纹肌肉瘤（RMS）中的YE / SRC家族酪氨酸激酶（SFK）的活化增加有关。将具有SFK抑制剂的抗IGF-1R试剂组合导致IGF-1R抑制诱导的是/ SFK的激活并在体外和体内显示有利的抗肿瘤活性。我们的数据提供了IGF-1R阻断的证据，导致在体外和体内激活是/ SRC系列激酶旁通抵抗途径。这可能具有特定的临床相关性，因为均是和IGF组分在RMS中过表达。增加是/ SFK活化可以作为临床生物标志物，用于预测肿瘤抗IGF-1R抑制。对IGF-1R和SFK的双重抑制可能对RMS患者具有更广泛和增强的临床益处。

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