The post-genomic era has seen many advances in our understanding of cancer pathways, yet resistance and tumor heterogeneity necessitate multiple approaches to target even monogenic tumors. Here, we combine phenotypic screening with chemical genetics to identify pre-messenger RNA endonuclease cleavage and polyadenylation specificity factor 3 (CPSF3) as the target of JTE-607, a small molecule with previously unknown target. We show that CPSF3 represents a synthetic lethal node in a subset of acute myeloid leukemia (AML) and Ewing's sarcoma cancer cell lines. Inhibition of CPSF3 by JTE-607 alters expression of known downstream effectors in AML and Ewing's sarcoma lines, upregulates apoptosis and causes tumor-selective stasis in mouse xenografts. Mechanistically, it prevents the release of newly synthesized pre-mRNAs, resulting in read-through transcription and the formation of DNA-RNA hybrid R-loop structures. This study implicates pre-mRNA processing, and specifically CPSF3, as a druggable target providing an avenue to therapeutic intervention in cancer.

中文翻译：

---

CPSF3 依赖的前 mRNA 加工作为 AML 和尤文肉瘤中的可药物节点。

后基因组时代在我们对癌症通路的理解方面取得了许多进展，但耐药性和肿瘤异质性需要多种方法来靶向甚至单基因肿瘤。在这里，我们将表型筛选与化学遗传学相结合，以确定前信使 RNA 核酸内切酶切割和多聚腺苷酸化特异性因子 3 (CPSF3) 作为 JTE-607 的靶标，JTE-607 是一种以前未知靶标的小分子。我们表明 CPSF3 代表急性髓性白血病 (AML) 和尤文氏肉瘤癌细胞系子集中的合成致死节点。JTE-607 对 CPSF3 的抑制会改变 AML 和尤文氏肉瘤系中已知下游效应子的表达，上调细胞凋亡并导致小鼠异种移植物中的肿瘤选择性停滞。从机制上讲，它阻止了新合成的前 mRNA 的释放，导致通读转录和DNA-RNA杂合R-环结构的形成。这项研究表明前 mRNA 加工，特别是 CPSF3，作为一种可药用靶标，为癌症的治疗干预提供了途径。