YES1 Is a Targetable Oncogene in Cancers Harboring YES1 Gene Amplification

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 esophage...

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Veröffentlicht in:Cancer research (Chicago, Ill.) Ill.), 2019-11, Vol.79 (22), p.5734-5745
Hauptverfasser: Hamanaka, Natsuki, Nakanishi, Yoshito, Mizuno, Takakazu, Horiguchi-Takei, Kana, Akiyama, Nukinori, Tanimura, Hiromi, Hasegawa, Masami, Satoh, Yasuko, Tachibana, Yukako, Fujii, Toshihiko, Sakata, Kiyoaki, Ogasawara, Kiyomoto, Ebiike, Hirosato, Koyano, Hiroshi, Sato, Haruhiko, Ishii, Nobuya, Mio, Toshiyuki
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Sprache:eng
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Zusammenfassung: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 ( ) as having a significant impact on tumor growth. An analysis of clinical samples showed that 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 -amplified cancers and . Yes-associated protein 1 (YAP1) played a role downstream of YES1 and contributed to the growth of -amplified 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 -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. .
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.CAN-18-3376