BMP5—受体相关分子影响NSCLC细胞EGFR-TKI耐药的分子机制研究

具有EGFR突变的NSCLC发生EGFR-TKI耐药的分子机制并不十分清楚。我们发现，携带相同EGFR激酶区突变类型的H1650与HCC4006、HCC827细胞对Gefitinib的敏感性相差近千倍。我们推测在某些EGFR突变的细胞中，存在某些分子/通路可以维持NSCLC细胞生长并导致对EGFR-TKI耐受。基因表达谱芯片数据显示，以BMP5为配体的TGFβ通路相关基因在H1650中显著高表达。体外实验也证实BMP5蛋白可以促进MEK和AKT磷酸化升高。据此，我们假设：BMP5及其受体分子在部分NSCLC细胞中高表达以维持细胞生长所依赖的关键信号通路，绕过EGFR等RTK通路的信号传导作用而使细胞对EGFR-TKI产生耐药。本项目将进一步从细胞学水平、临床样本水平深入细致地研究BMP5-受体通路与EGFR-TKI耐药的关系，并为EGFR突变的NSCLC患者的个体化治疗提供理论依据。

Resistances to EGFR Tyrosine Kinase Inhibitors (EGFR-TKI) have frequently occured in NSCLC with EGFR mutation, while its molecular mechanisms are not clearly understood. Our data revealed that H1650 was more resistant to gefitinib than HCC4006 and HCC827, even through the three cells harbor a same EGFR mutation of 19 exon deletion. Thus, we proposed that there might be some other keys molecules or pathways which play key roles in EGFR-TKI resistance in a part of EGFR-mutated NSCLC cells. Analyzing the gene-expression profile we found that, BMP5 and related genes in TGFβ signaling pathway were up-regulated in H1650 than HCC4006 and HCC827. Furthermore, recombinant BMP-5 could stimulate the elevation of phospho levels of AKT and MEK in H1650. Thus, we proposed the following assumption: high expression of BMP-5 and its receptors in a part of NSCLC cells could activate key downstream pathways which maintain cell growth and survival through bypassing the EGFR signaling, and then lead to EGFR-TKI resistance. To uncover this assumption, this study will further exam the detailed molecular mechanisms between BMP5-receptors and EGFR-TKI resistance based on cytology and clinical specimin levels. The results are expected to provide novel evidence for individual treatment of EGFR-mutated NSCLC patients.