Razi Tooba, Farrell Ally C, Campos Gudiño Rubi, Neudorf Nicole M, Lichtensztejn Zelda, McManus Kirk J
Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada.
Paul Albrechtsen Research Institute CancerCare Manitoba, Winnipeg, MB, Canada.
Mol Ther Oncol. 2025 Aug 5;33(3):201028. doi: 10.1016/j.omton.2025.201028. eCollection 2025 Sep 18.
Colorectal cancer (CRC) remains a leading cause of cancer mortality worldwide, with chromosome instability (CIN) present in approximately 85% of cases and associated with poor prognosis. Reduced expression of , a component of the SKP1-CUL1-F-box (SCF) E3 ubiquitin ligase complex, occurs in about one-third of CRCs and correlates with CIN, positioning as a potential therapeutic target. This study employed bioinformatics analyses, small interfering RNA (siRNA) screening, small molecule inhibition, and quantitative imaging (QuantIM) microscopy to identify synthetic lethal interactors of . Shallow deletions of in CRC patient samples was found to associate with decreased gene expression and adverse clinical outcomes. Targeted silencing or pharmacological inhibition of CHEK1 using Prexasertib significantly reduced proliferation in -deficient cells. Mechanistic studies revealed that Prexasertib treatment increased DNA double-strand breaks and apoptosis specifically in -deficient cells. Furthermore, combining Prexasertib with 5-fluorouracil, a standard chemotherapeutic agent, produced a synergistic killing effect. These findings establish a novel synthetic lethal relationship between and , suggesting that CHEK1 inhibition may provide a targeted therapeutic strategy for CRC patients with deficiencies, and highlighting the broader potential of exploiting SCF complex alterations in CRC therapy.
结直肠癌（CRC）仍是全球癌症死亡的主要原因，约85%的病例存在染色体不稳定（CIN），且与预后不良相关。SKP1-CUL1-F盒（SCF）E3泛素连接酶复合体的一个组成部分——[具体基因名称缺失]的表达降低，约三分之一的结直肠癌中出现这种情况，并且与CIN相关，这使得[具体基因名称缺失]成为一个潜在的治疗靶点。本研究采用生物信息学分析、小分子干扰RNA（siRNA）筛选、小分子抑制和定量成像（QuantIM）显微镜技术来鉴定[具体基因名称缺失]的合成致死相互作用因子。在结直肠癌患者样本中发现[具体基因名称缺失]的浅缺失与基因表达降低和不良临床结果相关。使用Prexasertib靶向沉默或药理抑制CHEK1可显著降低[具体基因名称缺失]缺陷细胞的增殖。机制研究表明，Prexasertib处理特异性地增加了[具体基因名称缺失]缺陷细胞中的DNA双链断裂和凋亡。此外，将Prexasertib与标准化疗药物5-氟尿嘧啶联合使用产生了协同杀伤作用。这些发现确立了[具体基因名称缺失]和[具体基因名称缺失]之间一种新的合成致死关系，表明抑制CHEK1可能为存在[具体基因名称缺失]缺陷的结直肠癌患者提供一种靶向治疗策略，并突出了在结直肠癌治疗中利用SCF复合体改变的更广泛潜力。
