Inhibition of Hsp90 down-regulates mutant epidermal growth factor receptor (EGFR) expression and sensitizes EGFR mutant tumors to paclitaxel
Inhibition of Hsp90 down-regulates mutant epidermal growth factor receptor (EGFR) expression and sensitizes EGFR mutant tumors to paclitaxel
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DOI：
10.1158/0008-5472.can-07-1570
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发表时间：
2008-01-15
期刊：
影响因子：
11.2
通讯作者：
Solit, David B.
中科院分区：
文献类型：
--
作者：
Sawai, Ayana;Chandarlapaty, Sarat;Solit, David B.
表皮生长因子受体（EGFR）激酶结构域的突变在肺癌患者亚组中发现，并与EGFR酪氨酸激酶抑制剂（TKI）的反应相关。对这些药物的耐药性总是会发展，目前的治疗策略在这种情况下疗效有限。Hsp 90抑制剂，如17-烯丙基氨基-17-脱甲氧基格尔德霉素（17-AAG），诱导EGFR和其它Hsp 90相互作用蛋白的降解，因此可用于依赖于敏感Hsp 90客户的肿瘤。我们发现，在对EGFR TKI有反应的肺腺癌患者中最常见的EGFR突变可被17-AAG有效降解。虽然野生型EGFR的表达也被17-AAG下调，但其降解需要更高浓度的药物和更长的药物暴露时间。在动物模型中，单剂量的17-AAG足以诱导突变型EGFR的降解并抑制下游信号传导。17-在其最大耐受剂量下，AAG治疗引起H3255（1，85811 EGFR）异种移植物生长的显著延迟，但不如EGFR TKI吉非替尼有效。17-AAG单独延迟，但不完全抑制，H1650和H1975异种移植物的生长，这两种EGFR突变体模型显示中等和高水平的吉非替尼抗性。17-AAG可以安全地与紫杉醇联合给药，并且联合用药比单独使用任何一种药物都更有效。这些数据表明，Hsp 90抑制联合化疗可能是肿瘤表达EGFR激酶结构域突变（包括EGFR TKI新发和获得性耐药）患者的有效治疗策略。
Mutations in the kinase domain of the epidermal growth factor receptor (EGFR) are found in a subset of patients with lung cancer and correlate with response to EGFR tyrosine kinase inhibitors (TKI). Resistance to these agents invariably develops, and current treatment strategies have limited efficacy in this setting. Hsp90 inhibitors, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG), induce the degradation of EGFR and other Hsp90 interacting proteins and may thus have utility in tumors dependent upon sensitive Hsp90 clients. We find that the EGFR mutations found most commonly in patients with lung adenocarcinoma who respond to EGFR TKIs are potently degraded by 17-AAG. Although the expression of wild-type EGFR was also down-regulated by 17-AAG, its degradation required higher concentrations of drug and a longer duration of drug exposure. In animal models, a single dose of 17-AAG was sufficient to induce degradation of mutant EGFR and inhibit downstream signaling. 17-AAG treatment, at its maximal tolerated dose, caused a significant delay in H3255 (1,85811 EGFR) xenograft growth but was less effective than the EGFR TKI gefitinib. 17-AAG alone delayed, but did not completely inhibit, the growth of H1650 and H1975 xenografts, two EGFR mutant models which show intermediate and high levels of gefitinib resistance. 17-AAG could be safely coadministered with paclitaxel, and the combination was significantly more effective than either drug alone. These data suggest that Hsp90 inhibition in combination with chemotherapy may represent an effective treatment strategy for patients whose tumors express EGFR kinase domain mutations, including those with de novo and acquired resistance to EGFR TKIs.