ERK phosphorylation is predictive of resistance to IGF-1R inhibition in small cell lung cancer.
ERK phosphorylation is predictive of resistance to IGF-1R inhibition in small cell lung cancer.
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DOI：
10.1158/1535-7163.mct-12-0618
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发表时间：
2013-06
影响因子：
5.7
通讯作者：
Rudin CM
中科院分区：
文献类型：
--
作者：
Zinn RL;Gardner EE;Marchionni L;Murphy SC;Dobromilskaya I;Hann CL;Rudin CM
迫切需要新的治疗方法来改善小细胞肺癌（SCLC）患者的预后。IGF-1 R抑制是SCLC的潜在治疗策略：IGF-1 R通路通常在SCLC中上调，并且通过下游信号通路（包括PI 3 K-Akt和MAPK）与细胞凋亡抑制和增殖刺激相关。为了评估对IGF-1 R抑制反应的潜在决定因素，我们评估了19种SCLC细胞系对OSI-906的相对敏感性，OSI-906是IGF-1 R和密切相关的胰岛素受体（IR）的小分子抑制剂。这些细胞系中约有三分之一对OSI-906敏感，IC 50 < 1 μM。IGF-1 R、IR、IGF-1、IGF-2、IGFBP 3和IGFBP 6的细胞系表达与对OSI-906的敏感性无关。有趣的是，OSI-906敏感系相对于抗性系表达显著较低水平的基线磷酸化ERK（p=0.006）。OSI-906处理导致敏感和耐药细胞系中磷酸化IGF-1 R和磷酸化Akt的剂量依赖性抑制，但仅在敏感细胞系中诱导凋亡和细胞周期停滞。我们在小鼠中使用NCI-H187异种移植物模型和两个SCLC患者异种移植物测试了OSI-906的体内功效。与模拟处理的动物相比，OSI-906处理导致NCI-H187中50%的肿瘤生长抑制和原发性患者异种移植物模型中30%的抑制。总之，我们的数据支持IGF-1 R抑制作为一个可行的治疗策略，为一个确定的小细胞肺癌的子集，并表明，低水平的磷酸化ERK预处理可能是这种治疗方法的敏感性指标。
New therapies are critically needed to improve the outcome for patients with small cell lung cancer (SCLC). IGF-1R inhibition is a potential treatment strategy for SCLC: the IGF-1R pathway is commonly upregulated in SCLC, and has been associated with inhibition of apoptosis and stimulation of proliferation through downstream signaling pathways including PI3K-Akt and MAPK. To evaluate potential determinants of response to IGF-1R inhibition, we assessed the relative sensitivity of 19 SCLC cell lines to OSI-906, a small molecule inhibitor of IGF-1R and the closely related insulin receptor (IR). Approximately one third of these cell lines were sensitive to OSI-906, with an IC50 < 1 μM. Cell line expression of IGF-1R, IR, IGF-1, IGF-2, IGFBP3, and IGFBP6 did not correlate with sensitivity to OSI-906. Interestingly, OSI-906 sensitive lines expressed significantly lower levels of baseline phospho-ERK relative to resistant lines (p=0.006). OSI-906 treatment resulted in dose-dependent inhibition of phospho-IGF-1R and phospho-Akt in both sensitive and resistant cell lines, but induced apoptosis and cell cycle arrest only in sensitive lines. We tested the in vivo efficacy of OSI-906 using an NCI-H187 xenograft model and two SCLC patient xenografts in mice. OSI-906 treatment resulted in 50% tumor growth inhibition in NCI-H187 and 30% inhibition in the primary patient xenograft models compared to mock treated animals. Taken together our data support IGF-1R inhibition as a viable treatment strategy for a defined subset of SCLC and suggest that low pretreatment levels of phospho-ERK may be indicative of sensitivity to this therapeutic approach.