Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.
Sci Transl Med. 2024 Jan 3;16(728):eade2774. doi: 10.1126/scitranslmed.ade2774.
Splicing modulation is a promising treatment strategy pursued to date only in splicing factor-mutant cancers; however, its therapeutic potential is poorly understood outside of this context. Like splicing factors, genes encoding components of the cohesin complex are frequently mutated in cancer, including myelodysplastic syndromes (MDS) and secondary acute myeloid leukemia (AML), where they are associated with poor outcomes. Here, we showed that cohesin mutations are biomarkers of sensitivity to drugs targeting the splicing factor 3B subunit 1 (SF3B1) H3B-8800 and E-7107. We identified drug-induced alterations in splicing, and corresponding reduced gene expression, of a number of DNA repair genes, including and , as the mechanism underlying this sensitivity in cell line models, primary patient samples and patient-derived xenograft (PDX) models of AML. We found that DNA damage repair genes are particularly sensitive to exon skipping induced by SF3B1 modulators due to their long length and large number of exons per transcript. Furthermore, we demonstrated that treatment of cohesin-mutant cells with SF3B1 modulators not only resulted in impaired DNA damage response and accumulation of DNA damage, but it sensitized cells to subsequent killing by poly(ADP-ribose) polymerase (PARP) inhibitors and chemotherapy and led to improved overall survival of PDX models of cohesin-mutant AML in vivo. Our findings expand the potential therapeutic benefits of SF3B1 splicing modulators to include cohesin-mutant MDS and AML.
剪接调控是一种有前途的治疗策略，迄今为止仅在剪接因子突变型癌症中进行了研究；然而，在这种背景之外，其治疗潜力还知之甚少。与剪接因子类似，编码黏合蛋白复合物组成部分的基因在癌症中经常发生突变，包括骨髓增生异常综合征（MDS）和继发性急性髓系白血病（AML），在这些疾病中，它们与不良预后相关。在这里，我们表明黏合蛋白突变是针对剪接因子 3B 亚基 1（SF3B1）H3B-8800 和 E-7107 靶向药物敏感的生物标志物。我们发现，在细胞系模型、原发性患者样本和 AML 的患者来源异种移植（PDX）模型中，药物诱导的剪接改变以及相应的许多 DNA 修复基因（包括 和 ）表达降低是这种敏感性的机制。我们发现，由于 DNA 损伤修复基因的长度较长且每个转录本的外显子数量较多，因此它们特别容易受到 SF3B1 调节剂诱导的外显子跳跃的影响。此外，我们证明，用 SF3B1 调节剂处理黏合蛋白突变细胞不仅导致 DNA 损伤反应受损和 DNA 损伤积累，而且还使细胞对随后的聚（ADP-核糖）聚合酶（PARP）抑制剂和化疗的杀伤变得敏感，并导致体内黏合蛋白突变 AML 的 PDX 模型的总生存率提高。我们的研究结果将 SF3B1 剪接调节剂的潜在治疗益处扩展到包括黏合蛋白突变型 MDS 和 AML。
