Division of Hematology and Oncology, University of California, San Francisco, CA 94143.
Helen Diller Comprehensive Cancer Center, University of California, San Francisco, CA 94115.
Proc Natl Acad Sci U S A. 2020 Aug 25;117(34):20776-20784. doi: 10.1073/pnas.2009137117. Epub 2020 Aug 11.
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（TFFs）存在于约 30%的软组织肉瘤中。TFFs 不易通过直接的药物治疗方式“靶向”，因此在临床上很难成为治疗目标。一个主要的例子是 CIC-DUX4 癌蛋白，它将 Capicua（CIC）与双同源框 4 基因（DUX4）融合。CIC-DUX4 肉瘤是一种高度侵袭性和致命性的小圆细胞肉瘤亚型，主要发生在青少年和年轻人中。为了在 CIC-DUX4 肉瘤中确定新的治疗靶点，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。我们发现了多个负调控 MAPK-ERK 信号的 CIC-DUX4 靶标。从机制上讲，CIC-DUX4 转录上调这些 MAPK 的负调节剂，以抑制 ERK 活性，从而导致持续的 CIC-DUX4 表达。通过抑制 DUSP6 对 MAPK-ERK 的遗传和药物激活导致 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准医学的策略来对抗这种致命的癌症。
