中心体扩增（CA）是细胞中中心体数量的异常增加，是肺部和其他恶性肿瘤中反复出现的现象。尽管 CA 通过诱导基因组不稳定性 (GIN) 促进肿瘤的发生和进展，但它也会诱导有丝分裂应激，从而危及细胞完整性。 CA 导致多极有丝分裂纺锤体的形成，从而导致致命的染色体分离错误。为了通过减轻 CA 的后果来维持 CA 的益处，恶性细胞依赖于代表治疗脆弱性的适应性机制。我们的目的是发现与肺癌 CA 相关的遗传依赖性。将 CRISPR/Cas9 功能基因组学筛选与肿瘤基因组分析相结合，我们确定了运动蛋白 KIFC1（也称为 HSET）是肺腺癌 (LUAD) 中特异的假定脆弱性。 KIFC1 表达与 LUAD 中的 CA 呈正相关，并与较差的患者预后、吸烟史和 GIN 指标相关。 KIFC1 功能丧失使具有高基础 KIFC1 表达的 LUAD 细胞对 CA 增强敏感，这与将额外中心体聚集成伪双极有丝分裂纺锤体的能力减弱有关。我们的工作表明，KIFC1 抑制代表了一种新方法，通过迫使细胞以多极纺锤体分裂，将 GIN 增强至 LUAD 中的致死水平，从而合理化进一步研究以调查其治疗潜力。© 2024。作者。

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.© 2024. The Author(s).