Wan Xiaolin, Yeung Choh, Heske Christine, Mendoza Arnulfo, Helman Lee J
Molecular Oncology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Molecular Oncology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
Neoplasia. 2015 Apr;17(4):358-66. doi: 10.1016/j.neo.2015.03.001.
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.
胰岛素样生长因子1受体（IGF-1R）由于其在促生存和抗凋亡信号传导中的重要作用，已成为多种实体癌的重要靶点。然而，对IGF-1R阻断产生耐药性是一个重大障碍，限制了临床治疗效果。在本研究中，我们确定了横纹肌肉瘤（RMS）对IGF-1R阻断剂R1507（一种抗IGF-1R抗体）和BMS-754807（一种IGF-1R/胰岛素受体（IR）小分子抑制剂）产生获得性耐药。我们发现，用IGF-IR抗体R1507或IR/IGF-IR激酶抑制剂BMS-754807治疗与横纹肌肉瘤（RMS）中YES/SRC家族酪氨酸激酶（SFK）的激活增加有关。将抗IGF-1R药物与SFK抑制剂联合使用可阻断IGF-1R抑制诱导的YES/SFK激活，并在体外和体内显示出有利的抗肿瘤活性。我们的数据表明，IGF-1R阻断在体外和体内均可导致YES/SRC家族激酶旁路耐药途径的激活。这可能具有特殊的临床意义，因为Yes和IGF成分在RMS中均过度表达。YES/SFK激活增加可能作为预测肿瘤对IGF-1R抑制耐药性的临床生物标志物。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。
