Understanding molecular mechanisms of Cetuximab insensitivity in Colorectal Cancer (CRC). Homo sapiens

Mutational status of KRAS in CRC is used to aid patient stratification for Cetuximab treatment. However, only a subset (10-40%) of patients with wt KRAS respond. We analyzed 40 mCRC tumors for Cetuximab response using a functional ex vivo platform. In the subset of non-responsive tumors, mutational (KRAS/BRAF and PIK3CA) and expression (AREG/EREG) analysis of key genes, transcriptomic profiling and GSEA were carried out to elucidate the molecular mechanisms underlying the response. Our analysis revealed deregulation of multiple pathways, notably Notch and Erbb2 and combined blockade of these two nodes elicited significant antitumor response. These findings collectively indicate the dependence of Cetuximab insensitive mCRC tumors on Notch and Erbb2 for survival and progression. Overall design: 8 Primary tumors tested in ex vivo platform for response to Cetuximab were subjected to expression analysis

结直肠癌（Colorectal Cancer, CRC）中KRAS基因的突变状态，可用于辅助西妥昔单抗（Cetuximab）治疗的患者分层。然而仅10%~40%的KRAS野生型患者可对该治疗产生应答。本研究采用功能性离体平台，对40例转移性结直肠癌（metastatic Colorectal Cancer, mCRC）肿瘤样本开展西妥昔单抗应答性分析。针对无应答的肿瘤亚组，本研究对关键基因进行了突变（KRAS/BRAF及PIK3CA）与表达（AREG/EREG）分析、转录组谱分析以及基因集富集分析（Gene Set Enrichment Analysis, GSEA），以阐明西妥昔单抗应答的潜在分子机制。本研究分析发现多条信号通路存在失调，其中以Notch与ERBB2通路尤为显著；联合阻断这两个通路节点可诱发显著的抗肿瘤应答。上述研究结果共同表明，西妥昔单抗不敏感的转移性结直肠癌肿瘤的生存与进展依赖于Notch与ERBB2通路。总体实验设计：对8例原发性结直肠癌肿瘤样本采用离体平台检测其西妥昔单抗应答性，并进行表达分析。