Division of Signaling and Functional Genomics, German Cancer Research Center (DKFZ), Department of Cell and Molecular Biology, Faculty of Medicine Mannheim, Heidelberg University, Heidelberg, Germany.
Department of Medicine II, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Int J Cancer. 2021 Apr 15;148(8):1948-1963. doi: 10.1002/ijc.33393. Epub 2020 Dec 4.
Tumor heterogeneity is a major challenge to the treatment of colorectal cancer (CRC). Recently, a transcriptome-based classification was developed, segregating CRC into four consensus molecular subtypes (CMS) with distinct biological and clinical characteristics. Here, we applied the CMS classification on CRC cell lines to identify novel subtype-specific drug vulnerabilities. We combined publicly available transcriptome data from multiple resources to assign 157 CRC cell lines to CMS. By integrating results from large-scale drug screens, we discovered that the CMS1 subtype is highly vulnerable to the BIRC5 suppressor YM155. We confirmed our results using an independent panel of CRC cell lines and demonstrated a 100-fold higher sensitivity of CMS1. This vulnerability was specific to YM155 and not observed for commonly used chemotherapeutic agents. In CMS1 CRC, low concentrations of YM155 induced apoptosis and expression signatures associated with ER stress-mediated apoptosis signaling. Using a genome-wide CRISPR/Cas9 screen, we further discovered a novel role of genes involved in LDL-receptor trafficking as modulators of YM155 sensitivity in the CRC cell line HCT116. Our work shows that combining drug response data with CMS classification in cell lines can reveal selective vulnerabilities and proposes YM155 as a novel subtype-specific drug.
肿瘤异质性是结直肠癌（CRC）治疗的主要挑战。最近，基于转录组的分类方法将 CRC 分为具有不同生物学和临床特征的四个共识分子亚型（CMS）。在这里，我们将 CMS 分类应用于 CRC 细胞系，以确定新的亚型特异性药物脆弱性。我们结合了来自多个资源的公开转录组数据，将 157 个 CRC 细胞系分配给 CMS。通过整合大规模药物筛选的结果，我们发现 CMS1 亚型对 BIRC5 抑制剂 YM155 高度敏感。我们使用独立的 CRC 细胞系验证了我们的结果，并证明 CMS1 的敏感性高 100 倍。这种脆弱性是 YM155 特有的，而不是常见的化疗药物所观察到的。在 CMS1 CRC 中，低浓度的 YM155 诱导细胞凋亡，并表达与 ER 应激介导的细胞凋亡信号相关的特征。使用全基因组 CRISPR/Cas9 筛选，我们进一步发现 LDL 受体运输相关基因在 CRC 细胞系 HCT116 中作为 YM155 敏感性调节剂的新作用。我们的工作表明，将药物反应数据与细胞系中的 CMS 分类相结合，可以揭示选择性脆弱性，并提出 YM155 作为一种新的亚型特异性药物。
