Transcription factor fusions (TFFs) are present in ∼30% of soft-tissue sarcomas. TFFs are not readily “druggable” in a direct pharmacologic manner and thus have proven difficult to target in the clinic. A prime example is the CIC-DUX4 oncoprotein, which fuses Capicua (CIC) to the double homeobox 4 gene, DUX4. CIC-DUX4 sarcoma is a highly aggressive and lethal subtype of small round cell sarcoma found predominantly in adolescents and young adults. To identify new therapeutic targets in CIC-DUX4 sarcoma, we performed chromatin immunoprecipitation sequencing analysis using patient-derived CIC-DUX4 cells. We uncovered multiple CIC-DUX4 targets that negatively regulate MAPK-ERK signaling. Mechanistically, CIC-DUX4 transcriptionally up-regulates these negative regulators of MAPK to dampen ERK activity, leading to sustained CIC-DUX4 expression. Genetic and pharmacologic MAPK-ERK activation through DUSP6 inhibition leads to CIC-DUX4 degradation and apoptotic induction. Collectively, we reveal a mechanism-based approach to therapeutically degrade the CIC-DUX4 oncoprotein and provide a precision-based strategy to combat this lethal cancer.

转录因子融合蛋白（TFF）存在于约30％的软组织肉瘤中。TFF不容易以直接的药理学方式“吸收”，因此已被证明很难在临床上靶向。一个主要的例子是CIC-DUX4癌蛋白，它将Capicua（CIC）与双重同源盒4基因DUX4融合。CIC-DUX4肉瘤是一种高度侵袭性和致死性的小圆形细胞肉瘤，主要见于青少年和年轻人。为了确定CIC-DUX4肉瘤中的新治疗靶标，我们使用患者来源的CIC-DUX4细胞进行了染色质免疫沉淀测序分析。我们发现了负调控MAPK-ERK信号的多个CIC-DUX4目标。从机制上讲，CIC-DUX4在转录上上调MAPK的这些负调控因子以抑制ERK活性，从而导致持续的CIC-DUX4表达。通过DUSP6抑制的遗传和药理学MAPK-ERK激活导致CIC-DUX4降解和凋亡诱导。总的来说，我们揭示了一种基于机制的方法来治疗性降解CIC-DUX4癌蛋白，并提供了一种基于精确度的策略来对抗这种致命的癌症。