Vancouver Prostate Centre, Vancouver, British Columbia, Canada.
Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Cancer Res. 2021 Apr 1;81(7):1681-1694. doi: 10.1158/0008-5472.CAN-20-2222. Epub 2021 Jan 13.
Low-grade serous ovarian carcinoma (LGSOC) is a rare tumor subtype with high case fatality rates in patients with metastatic disease. There is a pressing need to develop effective treatments using newly available preclinical models for therapeutic discovery and drug evaluation. Here, we use multiomics integration of whole-exome sequencing, RNA sequencing, and mass spectrometry-based proteomics on 14 LGSOC cell lines to elucidate novel biomarkers and therapeutic vulnerabilities. Comparison of LGSOC cell line data with LGSOC tumor data enabled predictive biomarker identification of MEK inhibitor (MEKi) efficacy, with KRAS mutations found exclusively in MEKi-sensitive cell lines and NRAS mutations found mostly in MEKi-resistant cell lines. Distinct patterns of Catalogue of Somatic Mutations in Cancer mutational signatures were identified in MEKi-sensitive and MEKi-resistant cell lines. Deletions of and genes were more frequent in cell lines than tumor samples and possibly represent key driver events in the absence of KRAS/NRAS/BRAF mutations. These LGSOC cell lines were representative models of the molecular aberrations found in LGSOC tumors. For prediction of MEKi efficacy, proteomic data provided better discrimination than gene expression data. Condensin, minichromosome maintenance, and replication factor C protein complexes were identified as potential treatment targets in MEKi-resistant cell lines. This study suggests that CDKN2A/B or MTAP deficiency may be exploited using synthetically lethal treatment strategies, highlighting the importance of using proteomic data as a tool for molecular drug prediction. Multiomics approaches are crucial to improving our understanding of the molecular underpinnings of LGSOC and applying this information to develop new therapies. SIGNIFICANCE: These findings highlight the utility of global multiomics to characterize LGSOC cell lines as research models, to determine biomarkers of MEKi resistance, and to identify potential novel therapeutic targets.
低级别浆液性卵巢癌 (LGSOC) 是一种罕见的肿瘤亚型，转移性疾病患者的病死率很高。迫切需要利用新获得的临床前模型来开发有效的治疗方法，以进行治疗发现和药物评估。在这里，我们使用全外显子组测序、RNA 测序和基于质谱的蛋白质组学对 14 种 LGSOC 细胞系进行多组学整合，以阐明新的生物标志物和治疗弱点。将 LGSOC 细胞系数据与 LGSOC 肿瘤数据进行比较，可鉴定出 MEK 抑制剂 (MEKi) 疗效的预测性生物标志物，发现 KRAS 突变仅存在于 MEKi 敏感的细胞系中，NRAS 突变主要存在于 MEKi 耐药的细胞系中。在 MEKi 敏感和 MEKi 耐药的细胞系中鉴定出不同的 Catalogue of Somatic Mutations in Cancer 突变特征模式。缺失基因和基因比肿瘤样本更频繁地发生在细胞系中，这可能代表在没有 KRAS/NRAS/BRAF 突变的情况下的关键驱动事件。这些 LGSOC 细胞系是 LGSOC 肿瘤中发现的分子异常的代表性模型。对于预测 MEKi 疗效，蛋白质组学数据比基因表达数据提供了更好的区分度。在 MEKi 耐药的细胞系中，发现有有丝分裂后期促进复合物、微染色体维持和复制因子 C 蛋白复合物可作为潜在的治疗靶点。这项研究表明，CDKN2A/B 或 MTAP 缺失可能可以通过合成致死治疗策略加以利用，突出了将蛋白质组学数据用作分子药物预测工具的重要性。多组学方法对于提高我们对 LGSOC 分子基础的理解以及应用这些信息来开发新疗法至关重要。
