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The Hsp90 inhibitor IPI-504 rapidly lowers EML4–ALK levels and induces tumor regression in ALK-driven NSCLC models

间变性淋巴瘤激酶 生物 癌症研究 Hsp90抑制剂 表皮生长因子受体 融合蛋白 热休克蛋白 热休克蛋白90 MAPK/ERK通路 肺癌 激酶 癌症 内科学 细胞生物学 医学 生物化学 基因 重组DNA 恶性胸腔积液 遗传学
作者
Emmanuel Normant,Guillermo Paez,Kip A. West,Alice R. Lim,Kelly L. Slocum,Chris Tunkey,James K. McDougall,Andrew Wylie,Keith Robison,K. Caliri,Vito J. Palombella,Christian Fritz
出处
期刊:Oncogene [Springer Nature]
卷期号:30 (22): 2581-2586 被引量:145
标识
DOI:10.1038/onc.2010.625
摘要

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.
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