Hsp90 inhibition suppresses mutant EGFR-T790M signaling and overcomes kinase inhibitor resistance.
Hsp90 inhibition suppresses mutant EGFR-T790M signaling and overcomes kinase inhibitor resistance.
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DOI：
10.1158/0008-5472.can-07-5428
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发表时间：
2008-07-15
期刊：
影响因子：
11.2
通讯作者：
Shapiro GI
中科院分区：
文献类型：
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作者：
Shimamura T;Li D;Ji H;Haringsma HJ;Liniker E;Borgman CL;Lowell AM;Minami Y;McNamara K;Perera SA;Zaghlul S;Thomas RK;Greulich H;Kobayashi S;Chirieac LR;Padera RF;Kubo S;Takahashi M;Tenen DG;Meyerson M;Wong KK;Shapiro GI
表皮生长因子受体（EGFR）二级激酶结构域T790 M非小细胞肺癌（NSCLC）突变增强受体催化活性，并赋予对可逆酪氨酸激酶抑制剂吉非替尼和厄洛替尼的耐药性。目前，不可逆抑制剂代表了临床使用中规避耐药性的主要方法。我们发现，与不含T790 M的EGFR突变型NSCLC细胞相比，需要更高浓度的不可逆EGFR抑制剂CL-387，785来抑制T790 M表达细胞中的EGFR磷酸化。此外，CL-387，785不能完全抑制T790 M表达细胞中其他活化受体酪氨酸激酶（RTK）的磷酸化。这些缺陷导致残留的Akt和哺乳动物雷帕霉素靶标（mTOR）活性。在T790 M表达细胞中EGFR介导的信号传导的完全抑制需要CL-387，785和雷帕霉素的组合。相比之下，Hsp 90抑制克服了体外的这些限制，并耗尽EGFR、其他RTK和磷酸化Akt的细胞，并抑制mTOR信号传导，无论T790 M是否存在。通过激酶转换机制对CL-387，785产生耐药性的EGFR-T790 M表达细胞保留对Hsp 90抑制的敏感性。最后，Hsp 90抑制导致由突变型EGFR（L 858 R）驱动的鼠肺腺癌消退，有或没有T790 M。然而，L 858 R-T790 M模型中的疗效需要更强烈的治疗方案，并且反应是短暂的。尽管如此，这些研究结果表明，热休克蛋白90抑制剂可能是有效的T790 M表达细胞，并提供了一个替代的治疗策略，这一子集的肺癌。
The epidermal growth factor receptor (EGFR) secondary kinase domain T790M non–small cell lung cancer (NSCLC) mutation enhances receptor catalytic activity and confers resistance to the reversible tyrosine kinase inhibitors gefitinib and erlotinib. Currently, irreversible inhibitors represent the primary approach in clinical use to circumvent resistance. We show that higher concentrations of the irreversible EGFR inhibitor CL-387,785 are required to inhibit EGFR phosphorylation in T790M-expressing cells compared with EGFR mutant NSCLC cells without T790M. Additionally, CL-387,785 does not fully suppress phosphorylation of other activated receptor tyrosine kinases (RTK) in T790M-expressing cells. These deficiencies result in residual Akt and mammalian target of rapamycin (mTOR) activities. Full suppression of EGFR-mediated signaling in T790M-expressing cells requires the combination of CL-387,785 and rapamycin. In contrast, Hsp90 inhibition overcomes these limitations in vitro and depletes cells of EGFR, other RTKs, and phospho-Akt and inhibits mTOR signaling whether or not T790M is present. EGFR-T790M– expressing cells rendered resistant to CL-387,785 by a kinase switch mechanism retain sensitivity to Hsp90 inhibition. Finally, Hsp90 inhibition causes regression in murine lung adenocarcinomas driven by mutant EGFR (L858R) with or without T790M. However, efficacy in the L858R-T790M model requires a more intense treatment schedule and responses were transient. Nonetheless, these findings suggest that Hsp90 inhibitors may be effective in T790M-expressing cells and offer an alternative therapeutic strategy for this subset of lung cancers.