Targeting KDM4 for treating PAX3-FOXO1-driven alveolar rhabdomyosarcoma.
Shivendra SinghAhmed Abu-ZaidHongjian JinJie FangQiong WuTingting WangHelin FengWaise QuarniYing ShaoLily MaxhamAlireza AbdolvahabiMi-Kyung YunSivaraja VaithiyalingamHaiyan TanJohn BowlingVictoria HonnellBrandon M YoungYian GuoRicha BajpaiShondra M Pruett-MillerGerard C GrosveldMark E HatleyBei-Si XuYiping FanGang WuEleanor Y ChenTaosheng ChenPeter W LewisZoran RankovicYimei LiAndrew Jackson MurphyJohn EastonJunmin PengXiang ChenRuoning WangStephen W WhiteAndrew M DavidoffJun J YangPublished in: Science translational medicine (2022)
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.