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Loss of histone lysine methyltransferase EZH2 confers resistance to tyrosine kinase inhibitors in non-small cell lung cancer.
Cancer Letters ( IF 9.1 ) Pub Date : 2020-09-10 , DOI: 10.1016/j.canlet.2020.09.003
Chuntao Quan 1 , Yuchen Chen 1 , Xiaomu Wang 1 , Dong Yang 1 , Qing Wang 2 , Yixue Huang 1 , Robert B Petersen 3 , Xinran Liu 1 , Ling Zheng 2 , Yangkai Li 4 , Kun Huang 1
Affiliation  

Tyrosine kinase inhibitor (TKI) treatment is the first-line therapy for non-small cell lung cancer (NSCLC) caused by activating mutations of epidermal growth factor receptor (EGFR). However, acquired resistance to EGFR-TKI occurs almost inevitably. Aberrant activation of proto-oncogene MET has been known to confer EGFR-TKI resistance; however, the mechanisms involved remains unclear. Recent evidence implicates epigenetic heterogeneity as playing roles in cancer drug resistance, whereas links involving epigenetic heterogeneity and MET in NSCLC remain poorly understood. We found that expression of EZH2, a histone methyltransferase, was negatively correlated with MET activation and EGFR-TKI resistance in NSCLC cells and clinical samples, suggesting the potential for EZH2 to be used as a biomarker for EGFR-TKI sensitivity. Knockdown or inhibition of EZH2 up-regulated MET expression and phosphorylation, and elevated proliferation and EGFR-TKI resistance of cells in vitro. Meanwhile, inhibition of MET or PI3K/AKT enhanced EZH2 levels and restored sensitivity to EGFR-TKI. These findings indicate a “MET-AKT-EZH2” feedback loop regulating EGFR-TKI-resistance. Furthermore, combination therapy of PI3K/AKT inhibition and EGFR-TKI, which interrupts the loop, enhanced tumor-suppressive effects in an EGFR-TKI-resistant xenograft model, indicating a potential approach against drug resistance in NSCLC.



中文翻译:

非小细胞肺癌中组蛋白赖氨酸甲基转移酶EZH2的丧失赋予了对酪氨酸激酶抑制剂的抗性。

酪氨酸激酶抑制剂(TKI)治疗是非小细胞肺癌(NSCLC)的一线治疗,它是由表皮生长因子受体(EGFR)的激活突变引起的。但是,对EGFR-TKI的获得性耐药几乎不可避免地发生。原癌基因MET的异常激活已知赋予EGFR-TKI抗性;但是,所涉及的机制仍不清楚。最近的证据暗示表观遗传异质性在癌症耐药中发挥作用,而涉及表观遗传异质性和MET的NSCLC之间的联系仍然知之甚少。我们发现,EZH2(一种组蛋白甲基转移酶)的表达与NSCLC细胞和临床样品中的MET激活和EGFR-TKI耐药性呈负相关,表明EZH2可能被用作EGFR-TKI敏感性的生物标记。敲低或EZH2的抑制上调MET表达和磷酸化,和升高的增殖和细胞的EGFR-TKI电阻体外。同时,抑制MET或PI3K / AKT可增强EZH2水平并恢复对EGFR-TKI的敏感性。这些发现表明“ MET-AKT-EZH2”反馈回路调节EGFR-TKI-抗性。此外,中断环的PI3K / AKT抑制和EGFR-TKI的联合治疗在EGFR-TKI耐药的异种移植模型中增强了肿瘤抑制作用,表明在NSCLC中潜在的耐药性方法。

更新日期:2020-09-23
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