英国癌症研究所Marco Gerlinger研究小组，探究了抗表皮生长因子受体(EGFR)治疗结直肠癌过程中，耐药和免疫系统进化的基因组和转录组决定因素。2019年7月8日出版的《癌细胞》杂志发表了这一最新研究成果。

研究组对35个RAS野生型CRCs中西妥昔单抗耐药情况的基因组和转录组分析，确定了NF1和非典型RAS/RAF畸变与主要耐药之间的关系，并验证了转录组CRC亚型作为非基因获益的预测因子。有获得性耐药的活组织检查中，60%的人没有携带任何基因耐药驱动因素。其中大多数已经从基线时西妥昔单抗敏感的转录组亚型转变为进展时富含成纤维细胞和生长因子的亚型。在体外，成纤维细胞上清赋予西妥昔单抗耐药性，证实了非遗传耐药性通过基质重塑的主要作用。西妥昔单抗治疗增加细胞毒性免疫浸润和PD-L1和LAG3免疫检查点表达，潜在地为免疫治疗西妥昔单抗耐药CRCs提供了机会。

据介绍，尽管存在生物标志物分层，但抗EGFR抗体西妥昔单抗仅对一组结直肠癌有效。

附：英文原文

Title: Genomic and Transcriptomic Determinants of Therapy Resistance and Immune Landscape Evolution during Anti-EGFR Treatment in Colorectal Cancer

Author: Andrew Woolston, Khurum Khan, Georgia Spain, Anguraj Sadanandam, David Cunningham, Marco Gerlinger

Issue&Volume: Jul 08, 2019 Volume 36Issue 1

Abstract: Despite biomarker stratification, the anti-EGFR antibody cetuximab is only effective against a subgroup of colorectal cancers (CRCs). This genomic and transcriptomic analysis of the cetuximab resistance landscape in 35 RAS wild-type CRCs identified associations of NF1 and non-canonical RAS/RAF aberrations with primary resistance and validated transcriptomic CRC subtypes as non-genetic predictors of benefit. Sixty-four percent of biopsies with acquired resistance harbored no genetic resistance drivers. Most of these had switched from a cetuximab-sensitive transcriptomic subtype at baseline to a fibroblast- and growth factor-rich subtype at progression. Fibroblast-supernatant conferred cetuximab resistance in vitro, confirming a major role for non-genetic resistance through stromal remodeling. Cetuximab treatment increased cytotoxic immune infiltrates and PD-L1 and LAG3 immune checkpoint expression, potentially providing opportunities to treat cetuximab-resistant CRCs with immunotherapy.

DOI: https://doi.org/10.1016/j.ccell.2019.05.013

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30255-7