Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
PLoS One. 2011;6(8):e23849. doi: 10.1371/journal.pone.0023849. Epub 2011 Aug 24.
The dismal lethality of lung cancer is due to late stage at diagnosis and inherent therapeutic resistance. The incorporation of targeted therapies has modestly improved clinical outcomes, but the identification of new targets could further improve clinical outcomes by guiding stratification of poor-risk early stage patients and individualizing therapeutic choices. We hypothesized that a sequential, combined microarray approach would be valuable to identify and validate new targets in lung cancer. We profiled gene expression signatures during lung epithelial cell immortalization and transformation, and showed that genes involved in mitosis were progressively enhanced in carcinogenesis. 28 genes were validated by immunoblotting and 4 genes were further evaluated in non-small cell lung cancer tissue microarrays. Although CDK1 was highly expressed in tumor tissues, its loss from the cytoplasm unexpectedly predicted poor survival and conferred resistance to chemotherapy in multiple cell lines, especially microtubule-directed agents. An analysis of expression of CDK1 and CDK1-associated genes in the NCI60 cell line database confirmed the broad association of these genes with chemotherapeutic responsiveness. These results have implications for personalizing lung cancer therapy and highlight the potential of combined approaches for biomarker discovery.
肺癌的死亡率高，主要是因为其在诊断时已处于晚期，且存在内在的治疗抵抗。靶向治疗的加入虽然略微改善了临床结果，但通过指导高危早期患者的分层和个体化治疗选择，确定新的靶点可能会进一步改善临床结果。我们假设，采用连续的、组合的微阵列方法将有助于识别和验证肺癌中的新靶点。我们在肺上皮细胞永生化和转化过程中对基因表达特征进行了分析，结果表明，有丝分裂相关基因在癌变过程中逐渐增强。通过免疫印迹验证了 28 个基因，进一步在非小细胞肺癌组织微阵列中评估了 4 个基因。尽管 CDK1 在肿瘤组织中高表达，但令人意外的是，其从细胞质中的丢失预示着较差的生存，并使多种细胞系对化疗产生耐药性，尤其是对微管导向药物。对 NCI60 细胞系数据库中 CDK1 和 CDK1 相关基因表达的分析证实了这些基因与化疗反应性的广泛相关性。这些结果对肺癌治疗的个体化具有重要意义，并强调了联合方法在生物标志物发现方面的潜力。
