Department of Molecular Pharmacology and Therapeutics, Oncology Institute, Loyola University of Chicago, Stritch School of Medicine, Maywood, Illinois, USA.
Clin Cancer Res. 2012 Sep 15;18(18):4973-85. doi: 10.1158/1078-0432.CCR-11-2967. Epub 2012 Jul 17.
We describe the anticancer activity of ganetespib, a novel non-geldanamycin heat shock protein 90 (HSP90) inhibitor, in non-small cell lung cancer (NSCLC) models.
The activity of ganetespib was compared with that of the geldanamycin 17-AAG in biochemical assays, cell lines, and xenografts, and evaluated in an ERBB2 YVMA-driven mouse lung adenocarcinoma model.
Ganetespib blocked the ability of HSP90 to bind to biotinylated geldanamycin and disrupted the association of HSP90 with its cochaperone, p23, more potently than 17-AAG. In genomically defined NSCLC cell lines, ganetespib caused depletion of receptor tyrosine kinases, extinguishing of downstream signaling, inhibition of proliferation and induction of apoptosis with IC(50) values ranging 2 to 30 nmol/L, substantially lower than those required for 17-AAG (20-3,500 nmol/L). Ganetespib was also approximately 20-fold more potent in isogenic Ba/F3 pro-B cells rendered IL-3 independent by expression of EGFR and ERBB2 mutants. In mice bearing NCI-H1975 (EGFR L858R/T790M) xenografts, ganetespib was rapidly eliminated from plasma and normal tissues but was maintained in tumor with t(1/2) 58.3 hours, supporting once-weekly dosing experiments, in which ganetespib produced greater tumor growth inhibition than 17-AAG. However, after a single dose, reexpression of mutant EGFR occurred by 72 hours, correlating with reversal of antiproliferative and proapoptotic effects. Consecutive day dosing resulted in xenograft regressions, accompanied by more sustained pharmacodynamic effects. Ganetespib also showed activity against mouse lung adenocarcinomas driven by oncogenic ERBB2 YVMA.
Ganetespib has greater potency than 17-AAG and potential efficacy against several NSCLC subsets, including those harboring EGFR or ERBB2 mutation.
我们描述了新型非格尔德霉素热休克蛋白 90（HSP90）抑制剂 ganetespib 在非小细胞肺癌（NSCLC）模型中的抗癌活性。
在生化测定、细胞系和异种移植中比较了 ganetespib 的活性与 geldanamycin 17-AAG 的活性，并在 ERBB2 YVMA 驱动的小鼠肺腺癌模型中进行了评估。
Ganetespib 阻断了 HSP90 与生物素化 geldanamycin 结合的能力，并比 17-AAG 更有效地破坏了 HSP90 与其共伴侣 p23 的关联。在基因组定义的 NSCLC 细胞系中，Ganetespib 导致受体酪氨酸激酶耗竭，下游信号失活，增殖抑制和凋亡诱导，IC（50）值范围为 2 至 30nmol/L，明显低于 17-AAG（20 至 3500nmol/L）所需的值。Ganetespib 在 Ba/F3 原 B 细胞中的活性也大约高 20 倍，这些细胞通过表达 EGFR 和 ERBB2 突变体而变得对 IL-3 不依赖。在携带 NCI-H1975（EGFR L858R/T790M）异种移植的小鼠中，Ganetespib 从血浆和正常组织中迅速消除，但在肿瘤中维持 t（1/2）为 58.3 小时，支持每周一次给药实验，其中 ganetespib 产生的肿瘤生长抑制作用大于 17-AAG。然而，单次给药后，72 小时内突变型 EGFR 重新表达，与抗增殖和促凋亡作用的逆转相关。连续每日给药导致异种移植物消退，并伴有更持续的药效学效应。Ganetespib 对由致癌性 ERBB2 YVMA 驱动的小鼠肺腺癌也有活性。
Ganetespib 的效力大于 17-AAG，对包括携带 EGFR 或 ERBB2 突变的 NSCLC 亚群在内的几种 NSCLC 亚型具有潜在疗效。
