USP8 is a novel target for overcoming gefitinib resistance in lung cancer.
USP8 is a novel target for overcoming gefitinib resistance in lung cancer.
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DOI：
10.1158/1078-0432.ccr-12-3696
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发表时间：
2013-07-15
期刊：
影响因子：
--
通讯作者：
Dong Z
中科院分区：
文献类型：
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作者：
Byun S;Lee SY;Lee J;Jeong CH;Farrand L;Lim S;Reddy K;Kim JY;Lee MH;Lee HJ;Bode AM;Won Lee K;Dong Z
非小细胞肺癌(NSCLC)的常见治疗方法包括表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)，如吉非替尼和厄洛替尼。然而，绝大多数接受治疗的患者对EGFR-TKIs产生了耐药性，这在很大程度上是由于EGFR的继发性突变或MET基因的扩增。我们的目的是测试泛素特异性多肽酶8(USP8)作为治疗吉非替尼耐药和敏感的非小细胞肺癌(NSCLC)的潜在靶点。在细胞培养和异种移植小鼠模型中，测试抑制USP8和使用合成的USP8抑制剂选择性地杀死对吉非替尼耐药(或敏感)的非小细胞肺癌细胞的效果，而对正常细胞几乎没有影响。敲除泛素特异性肽酶8(USP8)选择性地杀死对吉非替尼耐药的非小细胞肺癌细胞，而对正常细胞几乎没有毒性。USP8的基因沉默导致几种受体酪氨酸激酶(RTK)的下调，包括EGFR、ERBB2、ERBB3和MET。我们还发现，一种合成的USP8抑制剂通过减少RTK的表达显著降低了对吉非替尼耐药和敏感的NSCLC细胞的存活率，而对正常细胞没有影响。此外，在使用吉非替尼耐药和敏感的NSCLC细胞的小鼠异种移植模型中，USP8抑制剂的治疗导致肿瘤大小显著减少。我们的结果首次证明，抑制USP8活性或减少USP8表达可以选择性地杀死NSCLC细胞。我们建议USP8作为对吉非替尼耐药和敏感的非小细胞肺癌细胞的潜在治疗靶点。
Common treatment modalities for non-small cell lung cancer (NSCLC) involve the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib and erlotinib. However, the vast majority of treated patients acquire resistance to EGFR-TKIs, due in large part to secondary mutations in EGFR or amplification of the MET gene. Our purpose was to test ubiquitin-specific peptidase 8 (USP8) as a potential therapeutic target for gefitinib-resistant and -sensitive non-small cell lung cancer (NSCLC). Testing the effect of knockdown of USP8 and use of a synthetic USP8 inhibitor to selectively kill gefitinib-resistant (or -sensitive) NSCLCs with little effect on normal cells in cell culture and a xenograft mouse model. Knockdown of ubiquitin-specific peptidase 8 (USP8) selectively kills gefitinib-resistant NSCLCs, while having little toxicity toward normal cells. Genetic silencing of USP8 led to the down-regulation of several receptor tyrosine kinases (RTKs), including EGFR, ERBB2, ERBB3, and MET. We also determined that a synthetic USP8 inhibitor markedly decreased the viability of gefitinib-resistant and -sensitive NSCLC cells by decreasing RTK expression, while having no effect on normal cells. Moreover, treatment with a USP8 inhibitor led to significant reductions in tumor size in a mouse xenograft model using gefitinib-resistant and -sensitive NSCLC cells. Our results demonstrate for the first time that the inhibition of USP8 activity or reduction in USP8 expression can selectively kill NSCLC cells. We propose USP8 as a potential therapeutic target for gefitinib-resistant and -sensitive NSCLC cells.