The Hsp90 inhibitor IPI-504 rapidly lowers EML4-ALK levels and induces tumor regression in ALK-driven NSCLC models
The Hsp90 inhibitor IPI-504 rapidly lowers EML4-ALK levels and induces tumor regression in ALK-driven NSCLC models
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DOI：
10.1038/onc.2010.625
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发表时间：
2011-06-01
期刊：
影响因子：
8
通讯作者：
Fritz, C. C.
中科院分区：
文献类型：
--
作者：
Normant, E.;Paez, G.;Fritz, C. C.
热休克蛋白 90 (Hsp90) 是癌症治疗的新兴靶点，因为它在维持关键致癌信号蛋白的活性和稳定性方面发挥着重要作用。我们在此表明，棘皮动物微管相关蛋白样 4 (EML4)-间变性淋巴瘤激酶 (ALK) 融合蛋白被认为是约 5% 的非小细胞肺癌 (NSCLC) 患者的致癌驱动因素，它与细胞中的 Hsp90 相关，并且在细胞暴露于 IPI-504 时迅速降解。我们发现 EML4-ALK 对 Hsp90 抑制比 HER2 或突变表皮生长因子受体 (EGFR) 更敏感，其蛋白质降解抑制浓度 (IC) (50) 在低纳摩尔范围内。这种降解导致下游信号通路的有效抑制，并诱导携带 EML4-ALK 融合的细胞生长停滞和凋亡。为了建立 EML4-ALK 表达与 IPI-504 敏感性之间的因果关系，我们将 EML4-ALK cDNA 引入 HEK293 细胞，并表明融合蛋白的表达使细胞在体外和体内对 IPI-504 敏感。在含有 ALK 重排的人类 NSCLC 细胞系的异种移植模型中，我们在临床相关剂量的 IPI-504 下观察到肿瘤消退。最后，被选择对 ALK 激酶抑制剂具有抗性的细胞仍保留对 IPI-504 的敏感性。我们最近在 NSCLC 患者（特别是携带 ALK 重排的患者）的 2 期临床试验中观察到 IPI-504 作为单一药物的部分反应。这项研究为这些临床观察结果提供了分子解释。癌基因 (2011) 30, 2581-2586; doi：10.1038/onc.2010.625； 2011 年 1 月 24 日在线发布
Heat shock protein 90 (Hsp90) is an emerging target for cancer therapy due to its important role in maintaining the activity and stability of key oncogenic signaling proteins. We show here that the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion protein, presumed to be the oncogenic driver in about 5% of patients with non-small cell lung cancer (NSCLC), is associated with Hsp90 in cells and is rapidly degraded upon exposure of cells to IPI-504. We find EML4-ALK to be more sensitive to Hsp90 inhibition than either HER2 or mutant epidermal growth factor receptor (EGFR) with an inhibitory concentration (IC)(50) for protein degradation in the low nanomolar range. This degradation leads to a potent inhibition of downstream signaling pathways and to the induction of growth arrest and apoptosis in cells carrying the EML4-ALK fusion. To generate a causative link between the expression of EML4-ALK and sensitivity to IPI-504, we introduced an EML4-ALK cDNA into HEK293 cells and show that the expression of the fusion protein sensitizes cells to IPI-504 both in vitro and in vivo. In a xenograft model of a human NSCLC cell line containing the ALK rearrangement, we observe tumor regression at clinically relevant doses of IPI-504. Finally, cells that have been selected for resistance to ALK kinase inhibitors retain their sensitivity to IPI-504. We have recently observed partial responses to administration of IPI-504 as a single agent in a phase 2 clinical trial in patients with NSCLC, specifically in patients that carry an ALK rearrangement. This study provides a molecular explanation for these clinical observations. Oncogene (2011) 30, 2581-2586; doi:10.1038/onc.2010.625; published online 24 January 2011