Targeting EHMT2 reverses EGFR-TKI resistance in NSCLC by epigenetically regulating the PTEN/AKT signaling pathway.
Targeting EHMT2 reverses EGFR-TKI resistance in NSCLC by epigenetically regulating the PTEN/AKT signaling pathway.
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靶向 EHMT2 通过表观遗传调节 PTEN/AKT 信号通路逆转 NSCLC 中的 EGFR-TKI 耐药性。
DOI：
10.1038/s41419-017-0120-6
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发表时间：
2018-01-26
影响因子：
9
通讯作者：
Yang X
中科院分区：
文献类型：
--
作者：
Wang L;Dong X;Ren Y;Luo J;Liu P;Su D;Yang X
表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)耐药是非小细胞肺癌(NSCLC)治疗的主要障碍。表观遗传学改变已被证明与非小细胞肺癌的发生有关；然而，它们在EGFR-TKI耐药中的作用仍不清楚。在这里，我们发现一种EHMT2抑制剂，UNK0638，可以显著抑制耐EGFR-TKI的NSCLC细胞的生长并诱导其凋亡。此外，我们还发现在EGFR-TKI耐药的NSCLC细胞中，EHMT2的表达和酶活性水平都升高。此外，我们确定，基因或药物抑制EHMT2的表达增强了TKI的敏感性，并抑制了EGFR-TKI耐药的NSCLC细胞的迁移和肿瘤球体的形成。进一步的研究表明，EHMT2参与了PTEN的转录抑制，从而促进了AKT途径的激活。我们的临床研究证实了EHMT2与PTEN的负相关关系。此外，我们确定，在临床前EGFR-TKI耐药模型中，EHMT2抑制剂和Erlotinib的联合治疗导致了增强的抗肿瘤效果。我们还发现，EHMT2的高表达和PTEN的低表达可以预测NSCLC患者的总体存活率较低。综上所述，我们的研究结果表明，EHMT2通过调节PTEN/AKT通路促进非小细胞肺癌细胞对EGFR-TKI的耐药，提示EHMT2可能是临床治疗耐EGFR-TKI的NSCLC的靶点。
Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). Epigenetic alterations have been shown to be involved in NSCLC oncogenesis; however, their function in EGFR-TKI resistance remains uncharacterized. Here, we found that an EHMT2 inhibitor, UNC0638, can significantly inhibit cell growth and induce apoptosis in EGFR-TKI-resistant NSCLC cells. Additionally, we also found that EHMT2 expression and enzymatic activity levels were elevated in EGFR-TKI-resistant NSCLC cells. Moreover, we determined that genetic or pharmacological inhibition of EHMT2 expression enhanced TKI sensitivity and suppressed migration and tumor sphere formation in EGFR-TKI-resistant NSCLC cells. Further investigation revealed that EHMT2 contributed to PTEN transcriptional repression and thus facilitated AKT pathway activation. The negative relationship between EHMT2 and PTEN was confirmed by our clinical study. Furthermore, we determined that combination treatment with the EHMT2 inhibitor and Erlotinib resulted in enhanced antitumor effects in a preclinical EGFR-TKI-resistance model. We also found that high EHMT2 expression along with low PTEN expression can predict poor overall survival in patients with NSCLC. In summary, our findings showed that EHMT2 facilitated EGFR-TKI resistance by regulating the PTEN/AKT pathway in NSCLC cells, suggesting that EHMT2 may be a target in the clinical treatment of EGFR-TKI-resistant NSCLC.
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影响因子：
28.2
作者：
Takezawa K;Pirazzoli V;Arcila ME;Nebhan CA;Song X;de Stanchina E;Ohashi K;Janjigian YY;Spitzler PJ;Melnick MA;Riely GJ;Kris MG;Miller VA;Ladanyi M;Politi K;Pao W
通讯作者：
Pao W
抗性和新颖的靶标在非小细胞肺癌中介导对EGFR和C-MET酪氨酸激酶抑制剂的抗性。
影响因子：
3.7
作者：
Botting GM;Rastogi I;Chhabra G;Nlend M;Puri N
通讯作者：
Puri N
影响因子：
4.7
作者：
Molinari F;Frattini M
通讯作者：
Frattini M
影响因子：
5.7
作者：
Liu, Chia-Wen;Hua, Kuo-Tai;Tan, Ching-Ting
通讯作者：
Tan, Ching-Ting
影响因子：
7.3
作者：
Morgillo F;Della Corte CM;Fasano M;Ciardiello F
通讯作者：
Ciardiello F