Liu Peng, Jiao Feng, Zhang Zhenghua, Zhao Feilong, Cai Jinping, Chen Shiqing, Fu Tao, Li Min
Department of Colorectal Surgery, Changhai Hospital, Naval Medical University Shanghai, China.
Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University Shanghai, China.
Am J Cancer Res. 2022 Nov 15;12(11):5300-5314. eCollection 2022.
mutations lead to persistent activation of multiple downstream effectors that drive the cancer phenotype. Approximately 30%-50% of colorectal cancer (CRC) patients harbor mutations, which confer more aggressive tumor biology and shorter overall survival (OS), especially in microsatellite stable (MSS) metastatic CRC. Given that KRAS mutant protein has been proven difficult to target directly, identifying genes that function closely with and targeting these genes seems to be a promising therapeutic strategy for -mutated MSS CRC. Here, function-sensitive genes were identified by assessing the correlation between gene dependency scores from CRISPR knockout screens and mRNA expression in -mutated MSS CRC cell lines in the Cancer Cell Line Encyclopedia (CCLE) database. If the correlation coefficient was ≥ 0.6, the gene was considered a function-sensitive gene. Then function-sensitive genes related to prognosis were screened out in The Cancer Genome Atlas (TCGA) cohort, and the prognostic value was validated in the Gene Expression Omnibus (GEO) cohort. Single-sample gene set enrichment analysis (ssGSEA) was performed to investigate the potential mechanisms. PockDrug-Server was used to predict the druggability of candidate genes. The results showed that in 20 -mutated MSS CRC cell lines, 13 genes were identified as function-sensitive genes. Of these 13 genes, only BIK expression was significantly associated with progression-free survival (PFS) and OS, and the BIK-high patients had significantly poorer PFS (HR=3.18, P=0.020) and OS (HR=4.74, P=0.030) than the BIK-low patients. Multivariate Cox regression analysis revealed high BIK expression as an independent predictor for poorer prognosis in -mutated MSS CRC. The prognostic value of BIK was also successfully validated in a GEO cohort. The results of ssGSEA showed that the BIK-high group was more prone to strong metastasis activity than the BIK-low group. Pocket druggability prediction analysis presented that BIK had three druggable pockets, and their druggability scores were above 0.8. These findings suggested that BIK is a promising prognostic marker and therapeutic target in -mutated MSS CRC.
突变导致多个下游效应器的持续激活，从而驱动癌症表型。约30%-50%的结直肠癌（CRC）患者携带突变，这些突变赋予肿瘤更具侵袭性的生物学特性和更短的总生存期（OS），尤其是在微卫星稳定（MSS）转移性CRC中。鉴于KRAS突变蛋白已被证明难以直接靶向，识别与KRAS功能密切相关的基因并靶向这些基因似乎是KRAS突变型MSS CRC的一种有前景的治疗策略。在此，通过评估来自癌症细胞系百科全书（CCLE）数据库中CRISPR敲除筛选的基因依赖性评分与KRAS突变型MSS CRC细胞系中KRAS mRNA表达之间的相关性，确定了KRAS功能敏感基因。如果相关系数≥0.6，则该基因被视为KRAS功能敏感基因。然后在癌症基因组图谱（TCGA）队列中筛选出与预后相关的KRAS功能敏感基因，并在基因表达综合数据库（GEO）队列中验证其预后价值。进行单样本基因集富集分析（ssGSEA）以研究潜在机制。使用PockDrug-Server预测候选基因的成药可能性。结果显示，在20个KRAS突变型MSS CRC细胞系中，有13个基因被鉴定为KRAS功能敏感基因。在这13个基因中，只有BIK表达与无进展生存期（PFS）和OS显著相关，BIK高表达的患者比BIK低表达的患者PFS（HR=3.18，P=0.020）和OS（HR=4.74，P=0.030）显著更差。多变量Cox回归分析显示，高BIK表达是KRAS突变型MSS CRC预后较差的独立预测因素。BIK的预后价值也在一个GEO队列中成功得到验证。ssGSEA结果显示，BIK高表达组比BIK低表达组更倾向于具有强烈的转移活性。口袋成药可能性预测分析表明，BIK有三个可成药口袋，其成药可能性评分高于0.8。这些发现表明，BIK是KRAS突变型MSS CRC中有前景的预后标志物和治疗靶点。
