EZH2 Modifies Sunitinib Resistance in Renal Cell Carcinoma by Kinome Reprogramming.
EZH2 Modifies Sunitinib Resistance in Renal Cell Carcinoma by Kinome Reprogramming.
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DOI：
10.1158/0008-5472.can-17-0899
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发表时间：
2017-12-01
期刊：
影响因子：
11.2
通讯作者：
Pili R
中科院分区：
文献类型：
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作者：
Adelaiye-Ogala R;Budka J;Damayanti NP;Arrington J;Ferris M;Hsu CC;Chintala S;Orillion A;Miles KM;Shen L;Elbanna M;Ciamporcero E;Arisa S;Pettazzoni P;Draetta GF;Seshadri M;Hancock B;Radovich M;Kota J;Buck M;Keilhack H;McCarthy BP;Persohn SA;Territo PR;Zang Y;Irudayaraj J;Tao WA;Hollenhorst P;Pili R
对受体酪氨酸激酶抑制剂（RTKi）的获得性和内在耐药性是改善肾透明细胞癌（ccRCC）治疗的主要障碍。最近的报告表明，耐药性是由肿瘤适应通过表观遗传机制激活替代生存途径驱动的。组蛋白甲基转移酶EZH2在包括ccRCC在内的许多癌症中经常发生改变。为了评估其在ccRCC对RTKi的抗性中的作用，我们建立并表征了自发转移的、患者来源的异种移植物（PDX）模型，其对RTKI舒尼替尼具有固有抗性，但对VEGF治疗性抗体贝伐单抗不具有抗性。舒尼替尼保持其抗血管生成和抗转移活性，但由于激酶组重编程而失去其直接的抗肿瘤作用，这导致促凋亡和细胞周期调控靶基因的抑制。调节EZH2表达或活性抑制了某些RTK的磷酸化，恢复了舒尼替尼在获得性或内在抗性ccRCC模型中的抗肿瘤作用。总的来说，我们的研究结果强调EZH2是舒尼替尼耐药ccRCC治疗干预的合理靶点，也是这种疾病中RTKi反应的预测标志物。
Acquired and intrinsic resistance to receptor tyrosine kinase inhibitors (RTKi) represent a major hurdle in improving the management of clear cell renal cell carcinoma (ccRCC). Recent reports suggest that drug resistance is driven by tumor adaptation via epigenetic mechanisms that activate alternative survival pathways. The histone methyl transferase EZH2 is frequently altered in many cancers including ccRCC. To evaluate its role in ccRCC resistance to RTKi, we established and characterized a spontaneously metastatic, patient-derived xenograft (PDX) model that is intrinsically resistant to the RTKI sunitinib but not to the VEGF therapeutic antibody bevacizumab. Sunitinib maintained its anti-angiogenic and anti-metastatic activity but lost its direct anti-tumor effects due to kinome reprogramming, which resulted in suppression of pro-apoptotic and cell cycle regulatory target genes. Modulating EZH2 expression or activity suppressed phosphorylation of certain RTK, restoring the anti-tumor effects of sunitnib in models of acquired or intrinsically resistant ccRCC. Overall, our results highlight EZH2 as a rational target for therapeutic intervention in sunitinib-resistant ccRCC as well as a predictive marker for RTKi response in this disease.