Multimodality Approaches to Treat Hypoxic Non-Small Cell Lung Cancer (NSCLC) Microenvironment.
Multimodality Approaches to Treat Hypoxic Non-Small Cell Lung Cancer (NSCLC) Microenvironment.
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DOI：
10.1177/1947601912457025
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发表时间：
2012-02-01
期刊：
影响因子：
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通讯作者：
Bocchetta, Maurizio
中科院分区：
文献类型：
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作者：
Liang, Shuang;Galluzzo, Paola;Bocchetta, Maurizio
我们在体外和体内都发现，NSCLC细胞在缺氧微环境中的存活需要Notch-1信号。低氧肿瘤环境是NSCLC治疗的一个问题，因为它在癌症对化疗的耐药性、肿瘤复发和转移中起关键作用。在这里，我们在原位NSCLC模型中靶向缺氧肿瘤组织。我们使用3种药物抑制Notch-1/IGF-1 R/Akt-1轴：γ-分泌酶抑制剂或GSI（MRK-003）、针对人IGF-1 R的完全人源化抗体（MK-0646）和泛Akt抑制剂（MK-2206），单独或以各种组合，包括目前临床使用的治疗剂。与对照组相比，除Akt抑制外，所有治疗均显著延长了小鼠的中位生存期。GSI治疗引起缺氧肿瘤的特异性细胞死亡。从小鼠切除的肿瘤显示出缺氧标志物的显著减少。此外，GSI治疗导致向肝和脑的转移减少。MK-0646对低氧肿瘤环境没有特异性，但与对照组相比，治疗组小鼠的中位生存期显著增加。NSCLC细胞通过在体内和体外5种细胞系中特异性过度激活EGF-R来逃避MK-0646治疗。这种现象是在蛋白质稳定性水平上实现的。MK-0646治疗引起对它反应差的NSCLC细胞中厄洛替尼敏感性增加。MK-0646随后厄洛替尼的顺序治疗显著延长小鼠的中位生存期。当两种药物同时给药时，未观察到生存获益，并且该联合治疗证明不如MK-0646单药有效。我们的数据提供了新的信息，可能为人类临床试验的规划提供见解，可能用于NSCLC患者的维持治疗。
We found both in vitro and in vivo that survival of NSCLC cells in a hypoxic microenvironment requires Notch-1 signaling. A hypoxic tumor environment represents a problem for NSCLC treatment because it plays a critical role in cancer resistance to chemotherapy, tumor recurrence, and metastasis. Here we targeted hypoxic tumor tissue in an orthotopic NSCLC model. We inhibited the Notch-1/IGF-1R/Akt-1 axis using 3 agents: a gamma-secretase inhibitor or GSI (MRK-003), a fully humanized antibody against the human IGF-1R (MK-0646), and a pan-Akt inhibitor (MK-2206), alone or in various combinations including therapeutics currently in clinical use. All treatments but Akt inhibition significantly prolonged the median survival of mice compared with controls. GSI treatment caused specific cell death of hypoxic tumors. Tumors excised from mice displayed a significant reduction of markers of hypoxia. Moreover, GSI treatment caused reduced metastasis to the liver and brain. MK-0646 was not specific to a hypoxic tumor environment but substantially increased the median survival of treated mice compared with controls. NSCLC cells evaded MK-0646 treatment by specifically overactivating EGF-R both in vivo and in 5 cell lines in vitro. This phenomenon is achieved at the level of protein stability. MK-0646 treatment caused increased erlotinib sensitivity in NSCLC cells poorly responsive to it. Sequential treatment with MK-0646 followed by erlotinib prolonged median survival of mice significantly. When the 2 drugs were administered simultaneously, no survival benefit was observed, and this combination therapy proved less effective than MK-0646 used as single agent. Our data offer novel information that may provide insights for the planning of clinical trials in humans, likely for maintenance therapy of NSCLC patients.