Combination of splicing factor inhibitor and histone deacetylase inhibitor

SF3B1基因突变及其与癌症进展的相关性已在血液系统恶性肿瘤和黑色素瘤中被显示。我们评价了应用SF3B1的特异性抑制剂FR901464(FR)抑制结直肠癌(CRC)中SF3B1基因表达和SF3B1基因突变的意义。FR对结直肠癌细胞株具有较强的细胞毒作用。所有耐FR克隆均存在密码子1074的错义突变，在245例结直肠癌患者中未发现该突变。动物实验表明，FR的抗肿瘤作用受到毒性的限制，尽管具有SF3B1突变的FR抗性克隆的生长速度明显慢于其亲本细胞。基因芯片分析显示，FR抑制了与细胞周期、Fanconi贫血、同源重组、核苷酸切除修复相关的通路。未发现葡萄膜黑色素瘤中1074密码子SF3B1突变对选择性剪接的影响。这些结果表明，SF3B1是治疗结直肠癌的一个新的分子靶点。

SF3B1 gene mutations and their relevance to cancer progression have been shown in hematological malignancies and melanoma. We assessed the significance of inhibition of SF3B1 gene expression and SF3B1 gene mutation in colorectal cancer (CRC) using FR901464 (FR), a specific inhibitor of SF3B1. FR showed strong cytotoxicity in CRC cancer cell lines. All FR-resistant clones had the missense mutations in the codon 1074, which mutations have not been found in 245 CRC patients. Animal experiments showed antitumor effect by FR was limited by toxicity, although FR resistant clones with SF3B1 mutations grew significantly slowly than their parental cells. Microarray analysis showed FR inhibited pathways related with cell cycle, Fanconi anemia, homologous recombination, nucleotide excision repair. The influence of SF3B1 mutation of codon 1074 on alternative splicing has not been found like uveal melanoma. These results indicate that SF3B1 is a novel molecular target for CRC treatment.