H3 Biomedicine Inc., Cambridge, Massachusetts, USA.
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Nat Med. 2018 May;24(4):497-504. doi: 10.1038/nm.4493. Epub 2018 Feb 19.
Genomic analyses of cancer have identified recurrent point mutations in the RNA splicing factor-encoding genes SF3B1, U2AF1, and SRSF2 that confer an alteration of function. Cancer cells bearing these mutations are preferentially dependent on wild-type (WT) spliceosome function, but clinically relevant means to therapeutically target the spliceosome do not currently exist. Here we describe an orally available modulator of the SF3b complex, H3B-8800, which potently and preferentially kills spliceosome-mutant epithelial and hematologic tumor cells. These killing effects of H3B-8800 are due to its direct interaction with the SF3b complex, as evidenced by loss of H3B-8800 activity in drug-resistant cells bearing mutations in genes encoding SF3b components. Although H3B-8800 modulates WT and mutant spliceosome activity, the preferential killing of spliceosome-mutant cells is due to retention of short, GC-rich introns, which are enriched for genes encoding spliceosome components. These data demonstrate the therapeutic potential of splicing modulation in spliceosome-mutant cancers.
癌症的基因组分析已经确定了 RNA 剪接因子编码基因 SF3B1、U2AF1 和 SRSF2 中的反复点突变，这些突变赋予了功能改变。携带这些突变的癌细胞优先依赖于野生型（WT）剪接体功能，但目前临床上尚无针对剪接体的治疗靶点。在这里，我们描述了一种 SF3b 复合物的口服调节剂 H3B-8800，它能够强烈且优先地杀死剪接体突变的上皮和血液系统肿瘤细胞。H3B-8800 的这些杀伤作用是由于其与 SF3b 复合物的直接相互作用，这一点可以从携带编码 SF3b 成分的基因突变的耐药细胞中 H3B-8800 活性丧失得到证明。尽管 H3B-8800 调节 WT 和突变剪接体的活性，但对剪接体突变细胞的优先杀伤是由于富含剪接体成分编码基因的短、GC 丰富的内含子的保留。这些数据证明了剪接体突变癌症中剪接体调节的治疗潜力。
