PLK1被过度表达在急性髓系白血病（AML）中。PLK1抑制剂onvansertib（ONV）与脱氧胞苷（DAC）联合的1b期试验在复发/难治性（R/R）AML患者中展示了初步的安全性和疗效。本研究旨在鉴定R/R AML患者对ONV + DAC的反应的分子预测因子。共有44名R/R AML患者接受了ONV + DAC治疗，并被视为评估疗效的对象。基线时采集了骨髓（BM）样本进行基因组和转录组分析（n = 32）。从基因集富集分析（GSEA）的核心基因中得出了一个包含10个基因表达特征，用于预测对ONV + DAC的反应。基因特征在独立数据集中进行了评估，并用于识别相关突变基因。20%的患者实现了完全缓解，有或无造血计数恢复（CR/CRi），并且32%的患者骨髓爆发物减少了≥50％。对于对治疗有反应的患者，其线粒体功能和氧化磷酸化水平升高。基因特征与独立数据集中的仅DAC反应无关。通过将该特征应用于BeatAML队列（n = 399），我们发现预测的ONV + DAC反应与剪接因子（SF）突变之间存在正向相关。在1b/2期试验中，有SF突变（SRSF2，SF3B1）的患者具有较高的CR/CRi率（50％）与没有SF突变的患者相比（9％）。在R/R AML患者中，PLK1抑制剂ONV与DAC的联合可能是潜在的治疗方案，特别适用于高氧化磷酸化基因表达和SF突变的患者。©2023. 作者。

PLK1 is overexpressed in acute myeloid leukemia (AML). A phase 1b trial of the PLK1 inhibitor onvansertib (ONV) combined with decitabine (DAC) demonstrated initial safety and efficacy in patients with relapsed/refractory (R/R) AML. The current study aimed to identify molecular predictors of response to ONV + DAC in R/R AML patients. A total of 44 R/R AML patients were treated with ONV + DAC and considered evaluable for efficacy. Bone marrow (BM) samples were collected at baseline for genomic and transcriptomic analysis (n = 32). A 10-gene expression signature, predictive of response to ONV + DAC, was derived from the leading-edge genes of gene set enrichment analyses (GSEA). The gene signature was evaluated in independent datasets and used to identify associated mutated genes. Twenty percent of the patients achieved complete remission, with or without hematologic count recovery (CR/CRi), and 32% exhibited a ≥50% reduction in bone marrow blasts. Patients who responded to treatment had elevated mitochondrial function and OXPHOS. The gene signature was not associated with response to DAC alone in an independent dataset. By applying the signature to the BeatAML cohort (n = 399), we identified a positive association between predicted ONV + DAC response and mutations in splicing factors (SF). In the phase 1b/2 trial, patients with SF mutations (SRSF2, SF3B1) had a higher CR/CRi rate (50%) compared to those without SF mutations (9%). PLK1 inhibition with ONV in combination with DAC could be a potential therapy in R/R AML patients, particularly those with high OXPHOS gene expression and SF mutations.© 2023. The Author(s).