FS-93, an Hsp90 inhibitor, induces G2/M arrest and apoptosis via the degradation of client proteins in oncogene addicted and derived resistant cancer cells.
FS-93, an Hsp90 inhibitor, induces G2/M arrest and apoptosis via the degradation of client proteins in oncogene addicted and derived resistant cancer cells.
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FS-93 是一种 Hsp90 抑制剂，通过降解致癌基因成瘾和衍生的耐药癌细胞中的客户蛋白来诱导 G2/M 期停滞和细胞凋亡。
DOI：
10.18632/oncoscience.156
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Geng M
中科院分区：
文献类型：
--
作者：
Zhang L;Shen A;Wang L;Liu H;Chen D;Xiong B;Shen J;Geng M
热休克蛋白90（Hsp 90）的抑制可同时消除多种异常激活的致癌蛋白的信号传导，特别是突变或扩增的激酶，这为癌症治疗提供了一种有吸引力的方法。在此，我们描述了FS-93，一种有效的Hsp 90抑制剂，通过诱导G2/M期阻滞和凋亡来影响几种类型的癌基因成瘾的癌细胞的存活。从机制上讲，FS-93治疗触发了HER 2、EML 4-ALK和c-Met等关键客户蛋白的降解，从而消除了它们的下游信号通路。重要的是，FS-93单独规避MET扩增导致对EGFR抑制的获得性耐药性。我们的研究表明，靶向热休克蛋白90是一个有前途的替代治疗策略，在癌基因成瘾和衍生的耐药癌细胞。
Inhibition of heat shock protein 90 (Hsp90) abrogates signaling of multiple aberrantly activated oncogenic proteins simultaneously, particularly mutated or amplified kinases, which provides an attractive approach for cancer treatment. Here, we described that FS-93, a potent Hsp90 inhibitor, impacted the survival of several types of oncogene addicted cancer cells through inducing G2/M arrest and apoptosis. Mechanistically, FS-93 treatment triggered the degradation of key client proteins such as HER2, EML4-ALK and c-Met and thereby abolished their downstream signaling pathways. Importantly, FS-93 alone circumvented MET amplification contributed acquired resistance to EGFR inhibition. Our study implicates that targeting Hsp90 is a promising alternative therapeutic tactic in oncogene addicted and derived resistant cancer cells.