Colorectal Cancer Consensus Molecular Subtypes Translated to Preclinical Models Uncover Potentially Targetable Cancer Cell Dependencies
Colorectal Cancer Consensus Molecular Subtypes Translated to Preclinical Models Uncover Potentially Targetable Cancer Cell Dependencies
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DOI：
10.1158/1078-0432.ccr-17-1234
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发表时间：
2018-02-15
影响因子：
11.5
通讯作者：
Lothe, Ragnhild A.
中科院分区：
文献类型：
--
作者：
Sveen, Anita;Bruun, Jarle;Lothe, Ragnhild A.
目的：结直肠癌对标准肿瘤治疗的反应有限。基因表达为基础的共识分子亚型（CMS）提供了一个新的范例分层治疗和药物再利用，然而，药物发现目前有限的翻译CMS临床前models.Experimental设计：我们分析了CMS在原发性结直肠癌，细胞系，和患者来源的异种移植物（PDX）。对于临床前模型的分类，我们开发了一个优化的分类富集癌细胞内在基因表达信号，并进行高通量体外药物筛选（n = 459药物），以分析亚型特异性药物sensitivity.Results：每个CMS组的独特的分子和临床病理特征进行了验证，在一个单一的医院系列的409原发性结直肠癌。发现新的癌细胞适应性分类器在原发性肿瘤中表现良好，并应用于148个细胞系和32个PDX，这些结直肠癌模型显示重现了CMS组的生物学。对33个细胞系的药物筛选显示了亚型依赖性反应特征，证实了CMS 2上皮/典型组对EGFR和HER 2抑制剂的强烈反应，并揭示了CMS 1微卫星不稳定性/免疫和CMS 4间充质表型细胞对HSP 90抑制剂的强烈敏感性。这种关联在其他CMS预测的细胞系中进行了体外验证。5-氟尿嘧啶和拜鲁明联合治疗显示出缓解CMS 4 PDX模型中的化疗耐药性的潜力，这在化学敏感的CMS 2 PDX model.Conclusions中未见效果：我们提供了CMS分类到临床前模型的翻译，并揭示了在化疗耐药CMS 4组中靶向治疗再利用的潜力。(C)2017年AACR。
Purpose: Response to standard oncologic treatment is limited in colorectal cancer. The gene expression-based consensus molecular subtypes (CMS) provide a new paradigm for stratified treatment and drug repurposing; however, drug discovery is currently limited by the lack of translation of CMS to preclinical models.Experimental Design: We analyzed CMS in primary colorectal cancers, cell lines, and patient-derived xenografts (PDX). For classification of preclinical models, we developed an optimized classifier enriched for cancer cell-intrinsic gene expression signals, and performed high-throughput in vitro drug screening (n = 459 drugs) to analyze subtype-specific drug sensitivities.Results: The distinct molecular and clinicopathologic characteristics of each CMS group were validated in a single-hospital series of 409 primary colorectal cancers. The new, cancer cell-adapted classifier was found to perform well in primary tumors, and applied to a panel of 148 cell lines and 32 PDXs, these colorectal cancer models were shown to recapitulate the biology of the CMS groups. Drug screening of 33 cell lines demonstrated subtype-dependent response profiles, confirming strong response to EGFR and HER2 inhibitors in the CMS2 epithelial/canonical group, and revealing strong sensitivity to HSP90 inhibitors in cells with the CMS1 microsatellite instability/immune and CMS4 mesenchymal phenotypes. This association was validated in vitro in additional CMS-predicted cell lines. Combination treatment with 5-fluorouracil and luminespib showed potential to alleviate chemoresistance in a CMS4 PDX model, an effect not seen in a chemosensitive CMS2 PDX model.Conclusions: We provide translation of CMS classification to preclinical models and uncover a potential for targeted treatment repurposing in the chemoresistant CMS4 group. (C) 2017 AACR.