YES1 Is a Targetable Oncogene in Cancers Harboring YES1 Gene Amplification
YES1 Is a Targetable Oncogene in Cancers Harboring YES1 Gene Amplification
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DOI：
10.1158/0008-5472.can-18-3376
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发表时间：
2019-11-15
期刊：
影响因子：
11.2
通讯作者：
Mio, Toshiyuki
中科院分区：
文献类型：
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作者：
Hamanaka, Natsuki;Nakanishi, Yoshito;Mio, Toshiyuki
通过分子靶向药物（MTA）靶向癌基因的遗传改变是治疗癌症的有效方法。然而，对于包括食管癌在内的许多癌症，仍然没有临床 MTA 选择。我们使用短发夹RNA文库在食管癌细胞系KYSE70中筛选新的癌基因，并鉴定出YES原癌基因1（YES1）对肿瘤生长具有显着影响。对临床样本的分析表明，YES1基因扩增不仅存在于食道癌中，还存在于肺癌、头颈癌、膀胱癌和其他癌症中，这表明YES1将成为抗癌药物的一个有吸引力的靶标。由于目前还没有有效的YES1抑制剂，我们制备了一种YES1激酶抑制剂，CH6953755。 CH6953755 抑制 YES1 激酶可在体外和体内产生针对 YES1 扩增癌症的抗肿瘤活性。 Yes 相关蛋白 1 (YAP1) 在 YES1 下游发挥作用，并促进 YES1 扩增癌症的生长。 YES1通过控制YAP1的核转位和丝氨酸磷酸化来调节YAP1转录活性。这些发现表明，YES1 对 YAP1 的调节在 YES1 扩增的癌症中发挥着重要作用，并且 CH6953755 在此类癌症中具有治疗潜力。 意义：这些发现将 SRC 家族激酶 YES1 确定为食管癌的靶向癌基因，并描述了一种具有临床应用潜力的 YES1 新型抑制剂。
Targeting genetic alterations of oncogenes by molecular-targeted agents (MTA) is an effective approach for treating cancer. However, there are still no clinical MTA options for many cancers, including esophageal cancer. We used a short hairpin RNA library to screen for a new oncogene in the esophageal cancer cell line KYSE70 and identified YES proto-oncogene 1 (YES1) as having a significant impact on tumor growth. An analysis of clinical samples showed that YES1 gene amplification existed not only in esophageal cancer but also in lung, head and neck, bladder, and other cancers, indicating that YES1 would be an attractive target for a cancer drug. Because there is no effective YES1 inhibitor so far, we generated a YES1 kinase inhibitor, CH6953755. YES1 kinase inhibition by CH6953755 led to antitumor activity against YES1-amplified cancers in vitro and in vivo. Yes-associated protein 1 (YAP1) played a role downstream of YES1 and contributed to the growth of YES1amplified cancers. YES1 regulated YAP1 transcription activity by controlling its nuclear translocation and serine phosphorylation. These findings indicate that the regulation of YAP1 by YES1 plays an important role in YES1-amplified cancers and that CH6953755 has therapeutic potential in such cancers.Significance: These findings identify the SRC family kinase YES1 as a targetable oncogene in esophageal cancer and describe a new inhibitor for YES1 that has potential for clinical utility.