Wen Qing, Dunne Philip D, O'Reilly Paul G, Li Gerald, Bjourson Anthony J, McArt Darragh G, Hamilton Peter W, Zhang Shu-Dong
Centre for Cancer Research and Cell Biology, Queen's University Belfast, UK.
Northern Ireland Centre for Stratified Medicine, Biomedical Sciences Research Institute, Ulster University, C-TRIC, Londonderry, UK.
Oncotarget. 2017 Jan 10;8(2):3206-3225. doi: 10.18632/oncotarget.13884.
Colorectal cancer (CRC) is a life-threatening disease with high prevalence and mortality worldwide. The KRAS oncogene is mutated in approximately 40% of CRCs. While antibody based EGFR inhibitors (cetuximab and panitumumab) represent a major treatment strategy for advanced KRAS wild type (KRAS-WT) CRCs, there still remains no effective therapeutic course for advanced KRAS mutant (KRAS-MT) CRC patients.In this study, we employed a novel and comprehensive approach of gene expression connectivity mapping (GECM) to identify candidate compounds to target KRAS-MT tumors. We first created a combined KRAS-MT gene signature with 248 ranked significant genes using 677 CRC clinical samples. A series of 248 sub-signatures was then created containing an increasing number of the top ranked genes. As an input to GECM analysis, each sub-signature was translated into a statistically significant therapeutic drugs list, which was finally combined to obtain a single list of significant drugs.We identify four antihypertensive angiotensin II receptor blockers (ARBs) within the top 30 significant drugs indicating that these drugs have a mechanism of action that can alter the KRAS-MT CRC oncogenic signaling. A hypergeometric test (p-value = 6.57 × 10-6) confirmed that ARBs are significantly enriched in our results. These findings support the hypothesis that ARB antihypertensive drugs may directly block KRAS signaling resulting in improvement in patient outcome or, through a reversion to a KRAS wild-type phenotype, improve the response to anti-EGFR treatment. Antihypertensive angiotensin II receptor blockers are therefore worth further investigation as potential therapeutic candidates in this difficult category of advanced colorectal cancers.
结直肠癌（CRC）是一种在全球范围内具有高发病率和死亡率的危及生命的疾病。KRAS致癌基因在约40%的结直肠癌中发生突变。虽然基于抗体的表皮生长因子受体（EGFR）抑制剂（西妥昔单抗和帕尼单抗）是晚期KRAS野生型（KRAS-WT）结直肠癌的主要治疗策略，但对于晚期KRAS突变型（KRAS-MT）结直肠癌患者，仍然没有有效的治疗方案。在本研究中，我们采用了一种新颖且全面的基因表达连接图谱（GECM）方法来识别针对KRAS-MT肿瘤的候选化合物。我们首先使用677份结直肠癌临床样本创建了一个包含248个排名显著的基因的KRAS-MT基因特征组合。然后创建了一系列包含越来越多排名靠前基因的248个子特征组合。作为GECM分析的输入，每个子特征组合都被转化为一份具有统计学意义的治疗药物清单，最终将这些清单合并以获得一份单一的显著药物清单。我们在排名前30的显著药物中识别出四种抗高血压血管紧张素II受体阻滞剂（ARB），这表明这些药物具有可以改变KRAS-MT结直肠癌致癌信号传导的作用机制。超几何检验（p值 = 6.57 × 10-6）证实ARB在我们的结果中显著富集。这些发现支持了以下假设：ARB抗高血压药物可能直接阻断KRAS信号传导，从而改善患者预后，或者通过恢复到KRAS野生型表型，提高对抗EGFR治疗的反应。因此，抗高血压血管紧张素II受体阻滞剂作为这类难治性晚期结直肠癌潜在的治疗候选药物值得进一步研究。
