Targeting KDM4 for treating PAX3-FOXO1–driven alveolar rhabdomyosarcoma
Shivendra V. Singh, Ahmed Abu‐Zaid, Hongjian Jin, Jie Fang, Qiong Wu, Tingting Wang, Helin Feng, Waise Quarni, Ying Shao, Lily Maxham, Alireza Abdolvahabi, Mi‐Kyung Yun, Sivaraja Vaithiyalingam, Haiyan Tan, John J. Bowling, Victoria Honnell, Brandon Young, Yian Guo, Richa Bajpai, Shondra M. Pruett‐Miller, Gerard C. Grosveld, Mark E. Hatley, Beisi Xu, Yiping Fan, Gang Wu, Eleanor Y. Chen, Taosheng Chen, Peter W. Lewis, Zoran Ranković, Yimei Li, Andrew J. Murphy, John Easton, Junmin Peng, Xiang Chen, Ruoning Wang, Stephen W. White, Andrew M. Davidoff, Jun Yang
Abstract
Chimeric transcription factors drive lineage-specific oncogenesis but are notoriously difficult to target. Alveolar rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue sarcoma transformed by the pathognomonic Paired Box 3–Forkhead Box O1 (PAX3-FOXO1) fusion protein, which governs a core regulatory circuitry transcription factor network. Here, we show that the histone lysine demethylase 4B (KDM4B) is a therapeutic vulnerability for PAX3-FOXO1 + RMS. Genetic and pharmacologic inhibition of KDM4B substantially delayed tumor growth. Suppression of KDM4 proteins inhibited the expression of core oncogenic transcription factors and caused epigenetic alterations of PAX3-FOXO1–governed superenhancers. Combining KDM4 inhibition with cytotoxic chemotherapy led to tumor regression in preclinical PAX3-FOXO1 + RMS subcutaneous xenograft models. In summary, we identified a targetable mechanism required for maintenance of the PAX3-FOXO1–related transcription factor network, which may translate to a therapeutic approach for fusion-positive RMS.