Glioblastoma (GBM) is a deadly brain tumor, and the kinesin motor KIF11 is an attractive therapeutic target with roles in proliferation and invasion. Resistance to KIF11 inhibitors, which has mainly been studied in animal models, presents significant challenges. We use lineage-tracing barcodes and single-cell RNA sequencing to analyze resistance in patient-derived GBM neurospheres treated with ispinesib, a potent KIF11 inhibitor. Similar to GBM progression in patients, untreated cells lose their neural lineage identity and become mesenchymal, which is associated with poor prognosis. Conversely, cells subjected to long-term ispinesib treatment exhibit a proneural phenotype. We generate patient-derived xenografts and show that ispinesib-resistant cells form less aggressive tumors in vivo, even in the absence of drug. Moreover, treatment of human ex vivo GBM slices with ispinesib demonstrates phenotypic alignment with in vitro responses, underscoring the clinical relevance of our findings. Finally, using retrospective lineage tracing, we identify drugs that are synergistic with ispinesib.

胶质母细胞瘤 (GBM) 是一种致命的脑肿瘤，驱动蛋白运动 KIF11 是一个有吸引力的治疗靶点，在增殖和侵袭中发挥作用。主要在动物模型中研究的 KIF11 抑制剂耐药性提出了重大挑战。我们使用谱系追踪条形码和单细胞 RNA 测序来分析经 ispinesib（一种有效的 KIF11 抑制剂）治疗的患者来源的 GBM 神经球的耐药性。与患者 GBM 进展类似，未经治疗的细胞会失去其神经谱系特征并变成间充质细胞，这与预后不良有关。相反，接受长期 ispinesib 治疗的细胞表现出原神经表型。我们生成了源自患者的异种移植物，并表明即使在没有药物的情况下，ispinesib 耐药细胞在体内也会形成侵袭性较小的肿瘤。此外，用 ispinesib 对人离体GBM 切片进行处理，显示出与体外反应的表型一致性，强调了我们的研究结果的临床相关性。最后，通过回顾性谱系追踪，我们确定了与 ispinesib 具有协同作用的药物。