The HSP90 inhibitor NVP-AUY922 potently inhibits non-small cell lung cancer growth.
The HSP90 inhibitor NVP-AUY922 potently inhibits non-small cell lung cancer growth.
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DOI：
10.1158/1535-7163.mct-12-0998
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发表时间：
2013-06
影响因子：
5.7
通讯作者：
Slamon DJ
中科院分区：
文献类型：
--
作者：
Garon EB;Finn RS;Hamidi H;Dering J;Pitts S;Kamranpour N;Desai AJ;Hosmer W;Ide S;Avsar E;Jensen MR;Quadt C;Liu M;Dubinett SM;Slamon DJ
热休克蛋白90(HSP90)参与蛋白质折叠，并作为许多客户蛋白的伴侣，其中许多在非小细胞肺癌(NSCLC)的发病机制中起重要作用。我们试图定义HSP90抑制剂NVP-AUY922的临床前效应，并确定应答的预测因素。我们在体外研究了NVP-AUY922对非小细胞肺癌细胞系增殖和蛋白表达的影响。我们评估了NVP-AUY922暴露引起的基因表达变化。对异种移植模型的肿瘤控制和生物学效应进行了评估。NVP-AUY922对41株NSCLC细胞体外生长均有明显的抑制作用，IC50和100 NM检测结果表明，NVP-AUY922对所有41株NSCLC细胞均有抑制作用。IC100(完全抑制增殖)+lt；40 nM在41个细胞系中有36个出现。NVP-AUY922暴露后持续的基因表达变化涉及广泛的细胞功能，包括暴露后持续降低的二氢叶酸还原酶(DHFR)。NVP-AUY922延缓了A549(KRAS突变体)移植瘤的生长，实现了肿瘤的稳定性，并降低了H1975异种移植瘤中表皮生长因子受体(EGFR)蛋白的表达，该模型含有EGFR基因中的EGFR酪氨酸激酶抑制剂的增敏和耐药突变。这些数据将有助于评估最近完成的NSCLC第二阶段试验和计划中的NVP-AUY922联合培美曲塞在NSCLC中的IB阶段试验的相关数据。
Heat shock protein 90 (HSP90) is involved in protein folding and functions as a chaperone for numerous client proteins, many of which are important in non-small cell lung cancer (NSCLC) pathogenesis. We sought to define preclinical effects of the HSP90 inhibitor NVP-AUY922 and identify predictors of response. We assessed in vitro effects of NVP-AUY922 on proliferation and protein expression in NSCLC cell lines. We evaluated gene expression changes induced by NVP-AUY922 exposure. Xenograft models were evaluated for tumor control and biological effects. NVP-AUY922 potently inhibited in vitro growth in all 41 NSCLC cell lines evaluated with IC50 < 100 nM. IC100 (complete inhibition of proliferation) < 40 nM was seen in 36 of 41 lines. Consistent gene expression changes after NVP-AUY922 exposure involved a wide range of cellular functions, including consistently decreased dihydrofolate reductase (DHFR) after exposure. NVP-AUY922 slowed growth of A549 (KRAS mutant) xenografts, and achieved tumor stability and decreased epidermal growth factor receptor (EGFR) protein expression in H1975 xenografts, a model harboring a sensitizing and a resistance mutation for EGFR tyrosine kinase inhibitors in the EGFR gene. This data will help inform the evaluation of correlative data from a recently completed phase II NSCLC trial and a planned phase IB trial of NVP-AUY922 in combination with pemetrexed in NSCLC.