Rubicon抑制EGFR的降解导致非小细胞肺癌进展

我们曾首次报道在非小细胞肺癌（NSCLC）中，活化的EGFR能磷酸化Beclin 1并增加其与自噬抑制蛋白Rubicon相互作用，从而抑制自噬促进肿瘤进展。Rubicon与Beclin 1复合体结合除抑制自噬外还能阻断次级内体与溶酶体结合。最近我们发现，在NSCLC细胞中活化的EGFR与Rubicon相互作用；EGFR在次级内体上积聚依赖Rubicon；Rubicon敲降导致EGFR的溶酶体降解和细胞癌活降低；在临床上Rubicon高表达与病人预后不良相关。据此我们推测：在NSCLC中EGFR突变体通过招募Rubicon到次级内体上结合Beclin 1以逃离溶酶体降解，进而在次级内体上积聚导致肿瘤生长。本项目将：①解析EGFR利用Rubicon逃离溶酶体降解的分子机制；②探索在次级内体上积聚的EGFR引起肿瘤生长的分子信号；③展示以Rubicon为NSCLC治疗靶标的潜能。

Mutations in the epidermal growth factor receptor (EGFR) gene are the most common genomic drivers of non-small cell lung carcinomas (NSCLC). We previously reported that active EGFR directly regulates the core autophagy machinery, which may contribute to tumor progression and chemoresistance in non-small cell lung carcinomas(NSCLC). We found that active EGFR binds to Beclin 1, leading to its multisite phosphorylation, enhanced binding to inhibitory protein Rubicon, decreased VPS34 activity, and eventually autophagy inhibition. Here, based on the preliminary data collected on NSCLC cells, including 1）EGFR interacts with Rubicon in a kinase activity-dependent manner，2）EGFR accumulates on the late endosomes of active EGFR bearing HCC827 cells, 3) Rubicon depletion leads to lysosomal degradation of the endosomal EGFR, 4) Rubicon depletion leads to decreased cell proliferation, migration and invasion, and colony formation 5) High Rubicon mRNA expression correlates with poor prognosis of NSCLC patients, we speculate another signal that EGFR may regulate through Beclin 1 complex, which in parallel to EGFR-mediated autophagy inhibition, also contributes to NSCLC progression. We propose that active EGFR hijacks Rubicon to the late endosome to block Beclin 1 function in order to escape lysosomal degradation. The escaped EGFR may initiate signals that lead to tumor progression. Step by step, we will confirm our hypothesis with carefully planned experiments. We will also explore the pathways with which the endosomal accumulated EGFR may initiate tumor progression, and test if disrupting Rubicon/Beclin 1 interaction with competitive peptide will reduce the size of xenografts derived from TKI-resistant NSCLC cells. Our study will demonstrate that Rubicon/Beclin 1 interaction is a promising therapeutic target in NSCLC, which has the potential to overcome TKI resistance.