Netherlands Cancer Institute, Amsterdam, the Netherlands.
Wellcome Trust Sanger Institute, Hinxton, UK.
Clin Cancer Res. 2018 Jan 1;24(1):84-94. doi: 10.1158/1078-0432.CCR-17-1172. Epub 2017 Oct 23.
Despite intense research, treatment options for patients with mesothelioma are limited and offer only modest survival advantage. We screened a large panel of compounds in multiple mesothelioma models and correlated sensitivity with a range of molecular features to detect biomarkers of drug response. We utilized a high-throughput chemical inhibitor screen in a panel of 889 cancer cell lines, including both immortalized and primary early-passage mesothelioma lines, alongside comprehensive molecular characterization using Illumina whole-exome sequencing, copy-number analysis and Affymetrix array whole transcriptome profiling. Subsequent validation was done using functional assays such as siRNA silencing and mesothelioma mouse xenograft models. A subgroup of immortalized and primary MPM lines appeared highly sensitive to FGFR inhibition. None of these lines harbored genomic alterations of FGFR family members, but rather BAP1 protein loss was associated with enhanced sensitivity to FGFR inhibition. This was confirmed in an MPM mouse xenograft model and by BAP1 knockdown and overexpression in cell line models. Gene expression analyses revealed an association between BAP1 loss and increased expression of the receptors FGFR1/3 and ligands FGF9/18. BAP1 loss was associated with activation of MAPK signaling. These associations were confirmed in a cohort of MPM patient samples. A subgroup of mesotheliomas cell lines harbor sensitivity to FGFR inhibition. BAP1 protein loss enriches for this subgroup and could serve as a potential biomarker to select patients for FGFR inhibitor treatment. These data identify a clinically relevant MPM subgroup for consideration of FGFR therapeutics in future clinical studies. .
尽管进行了深入研究，但间皮瘤患者的治疗选择有限，仅提供适度的生存优势。我们在多种间皮瘤模型中筛选了大量化合物，并将敏感性与一系列分子特征相关联，以检测药物反应的生物标志物。我们利用高通量化学抑制剂筛选了 889 种癌细胞系的面板，包括永生和早期传代的间皮瘤系，以及使用 Illumina 全外显子组测序、拷贝数分析和 Affymetrix 芯片全转录组分析进行全面分子特征描述。随后使用功能测定（如 siRNA 沉默和间皮瘤小鼠异种移植模型）进行验证。一组永生和原代 MPM 系对 FGFR 抑制高度敏感。这些系均未携带 FGFR 家族成员的基因组改变，但 BAP1 蛋白丢失与对 FGFR 抑制的敏感性增强相关。这在 MPM 小鼠异种移植模型中以及在细胞系模型中通过 BAP1 敲低和过表达得到证实。基因表达分析显示 BAP1 丢失与 FGFR1/3 受体和配体 FGF9/18 的表达增加之间存在关联。BAP1 丢失与 MAPK 信号通路的激活相关。这些关联在一组 MPM 患者样本中得到证实。一小部分间皮瘤细胞系对 FGFR 抑制敏感。BAP1 蛋白丢失使该亚组富集，可作为选择 FGFR 抑制剂治疗患者的潜在生物标志物。这些数据确定了一个具有临床相关性的 MPM 亚组，可在未来的临床研究中考虑 FGFR 治疗。
