高度异质性是肺癌靶向治疗的难题。我们首次报道了肺癌细胞多具异常活跃的翻译起始行为，且mRNA的翻译起始效率（translation ratio, TR）与表型密切相关。故全局干预TR可能安全降低肺癌细胞的恶性表型。我们前期发现金精三羧酸铵盐（ATCA）可无细胞毒性全局降低TR，并在细胞株和小鼠体内抑制肺癌细胞恶性表型。因此，我们将针对占肺癌70-85%的非小细胞肺癌，以ATCA作用携EGFR L858R或K-RAS突变的6株肺癌细胞，开展翻译组、蛋白质组（包括总蛋白质、磷酸化和转录因子组）和转录组定量分析。揭示全局干预TR所致生物信息流定量变化规律，发现指征信息流的关键分子。进而以体外细胞模型和病人肿瘤组织的移植模型小鼠等体内模型验证ATCA对肺癌小鼠生存期和特征分子变化趋势。本项目有望在肺癌细胞mRNA翻译调控领域形成以分子系统干预为特色的新理论和临床研究方向。

Heterogeneity is a major concern in the field of lung cancer target therapy. We have reported that lung cancer cells have common characteristics in terms of highly active translation behaviors and translation initiation efficiency (translation ratio, TR), which is strongly relevant to phenotypes. Therefore, we hypothesize that systematic interference on TR can safely contain the malignant phenotypes of lung cancer cells. Our preliminary findings included in this proposal have suggested that aurintricarboxylic acid ammonium salt (ATCA) can systematically suppress TR with no observable cytotoxicity, while significantly inhibiting lung cancer cell proliferation, invasion and migration both in vitro and in vivo. Thus, ATCA tends to be a proper model drug for testing the hypothesis of this proposal. In this study, we will focus on non-small cell lung cancer (NSCLC), which represents 70-85% of lung cancer incidences. We will employ 6 NSCLC cell lines that carry EGFR L858R or K-RAS mutations. By treating them with ATCA, we will analyze their alterations in phenotypes, transcriptome, translatome and proteome, including analyses on total and phosphorylated proteins and transcription factors. We will answer how the genome-wide TR changes function on the multi-omics, and interrogate the systems biology mechanisms in terms of the flow of genetic information, protein-protein interaction networks, target biological functions, pathways and node molecules. Furthermore, we will validate these mechanisms with in vitro models as well as transgenic and xenograft mouse in vivo models. This study has its potentials to establish novel theories of systematic inference on lung cancer cell mRNA translation, which leads to promising directions of clinical researches.