文章：

将KIFC1确定为针对中心体扩增型肺癌的一个潜在弱点

Identification of KIFC1 as a putative vulnerability in lung cancers with centrosome amplification

原文发布日期：2024-08-24 

英文摘要：

Centrosome amplification (CA), an abnormal increase in the number of centrosomes in the cell, is a recurrent phenomenon in lung and other malignancies. Although CA promotes tumor development and progression by inducing genomic instability (GIN), it also induces mitotic stress that jeopardizes cellular integrity. CA leads to the formation of multipolar mitotic spindles that can cause lethal chromosome segregation errors. To sustain the benefits of CA by mitigating its consequences, malignant cells are dependent on adaptive mechanisms that represent therapeutic vulnerabilities. We aimed to discover genetic dependencies associated with CA in lung cancer. Combining a CRISPR/Cas9 functional genomics screen with tumor genomic analyses, we identified the motor protein KIFC1, also known as HSET, as a putative vulnerability specifically in lung adenocarcinoma (LUAD) with CA. KIFC1 expression was positively correlated with CA in LUAD and associated with worse patient outcomes, smoking history, and indicators of GIN. KIFC1 loss-of-function sensitized LUAD cells with high basal KIFC1 expression to potentiation of CA, which was associated with a diminished ability to cluster extra centrosomes into pseudo-bipolar mitotic spindles. Our work suggests that KIFC1 inhibition represents a novel approach for potentiating GIN to lethal levels in LUAD with CA by forcing cells to divide with multipolar spindles, rationalizing further studies to investigate its therapeutic potential. 

摘要翻译：

中心体扩增（CA）即细胞中中心体数量异常增加，是肺癌及其他恶性肿瘤中常见的现象。尽管CA通过诱导基因组不稳定性（GIN）促进肿瘤发生发展，但也会引发危及细胞完整性的有丝分裂应激。CA会导致多极纺锤体形成，进而引发致命的染色体分离错误。为通过减轻CA的负面影响来维持其促癌效益，恶性细胞依赖于代表治疗脆弱性的适应性机制。本研究旨在探索肺癌中CA相关的遗传依赖性。通过结合CRISPR/Cas9功能基因组学筛选与肿瘤基因组分析，我们发现运动蛋白KIFC1（又称HSET）是中心体扩增型肺腺癌（LUAD）的特异性潜在治疗靶点。在LUAD中，KIFC1表达与CA呈正相关，且与患者预后不良、吸烟史及GIN指标相关。KIFC1功能缺失使高基础KIFC1表达的LUAD细胞对CA增强效应敏感，这种敏感性与其将多余中心体聚类成伪双极纺锤体的能力减弱相关。我们的研究表明，抑制KIFC1可通过强制细胞进行多极纺锤体分裂，将GIN增强至致死水平，这为中心体扩增型LUAD提供了新型治疗策略，为后续探索其治疗潜力的研究提供了理论依据。

原文链接：

Identification of KIFC1 as a putative vulnerability in lung cancers with centrosome amplification