YES1 Is a Targetable Oncogene in Cancers Harboring <i>YES1</i> Gene Amplification.

Abstract

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 (<i>YES1</i>) as having a significant impact on tumor growth. An analysis of clinical samples showed that <i>YES1</i> 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 <i>YES1</i>-amplified cancers <i>in vitro</i> and <i>in vivo</i>. Yes-associated protein 1 (YAP1) played a role downstream of YES1 and contributed to the growth of <i>YES1</i>-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 <i>YES1</i>-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.<i>See related commentary by Rai, p. 5702</i>.