Introduction: Targeted therapies for lung adenocarcinoma (LUAD) have improved patient outcomes; however, drug resistance remains a major problem. One strategy to achieve durable response is to develop combination‐based therapies that target both mutated oncogenes and key modifiers of oncogene‐driven tumorigenesis. This is based on the premise that mutated oncogenes, although necessary, are not sufficient for malignant transformation. We aimed to uncover genetic alterations that cooperate with mutant EGFR during LUAD development. Methods: We performed integrative genomic analyses, combining copy number, gene expression and mutational information for over 500 LUAD tumors. Co‐immunoprecipitation and Western blot analysis were performed in LUAD cell lines to confirm candidate interactions while RNA interference and gene overexpression were used for in vitro and in vivo functional assessment. Results: We identified frequent amplifications/deletions of chromosomal regions affecting the activity of genes specifically in the context of EGFR mutation, including amplification of the mutant EGFR allele and deletion of dual specificity phosphatase 4 (DUSP4), which have both previously been reported. In addition, we identified the novel amplification of a segment of chromosome arm 16p in mutant‐EGFR tumors corresponding to increased expression of Golgi Associated, Gamma Adaptin Ear Containing, ARF Binding Protein 2 (GGA2), which functions in protein trafficking and sorting. We found that GGA2 interacts with EGFR, increases EGFR protein levels and modifies EGFR degradation after ligand stimulation. Furthermore, we show that overexpression of GGA2 enhances EGFR mediated transformation while GGA2 knockdown reduces the colony and tumor forming ability of EGFR mutant LUAD. Conclusions: These data suggest that overexpression of GGA2 in LUAD tumors results in the accumulation of EGFR protein and increased EGFR signaling, which helps drive tumor progression. Thus, GGA2 plays a cooperative role with EGFR during LUAD development and is a potential therapeutic target for combination‐based strategies in LUAD.

中文翻译：

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综合基因组分析确定 GGA2 是 EGFR 介导的肺肿瘤发生的协同驱动因素

简介：肺腺癌 (LUAD) 的靶向治疗改善了患者的预后；然而，耐药性仍然是一个主要问题。实现持久反应的一种策略是开发针对突变致癌基因和致癌基因驱动的肿瘤发生的关键修饰物的联合疗法。这是基于这样的前提，即突变的癌基因虽然是必要的，但不足以导致恶变。我们旨在揭示在 LUAD 发育过程中与突变 EGFR 合作的遗传改变。方法：我们对 500 多个 LUAD 肿瘤进行了综合基因组分析，结合了拷贝数、基因表达和突变信息。在 LUAD 细胞系中进行免疫共沉淀和蛋白质印迹分析以确认候选相互作用，而 RNA 干扰和基因过表达用于体外和体内功能评估。结果：我们确定了在 EGFR 突变的背景下影响基因活性的染色体区域的频繁扩增/缺失，包括突变 EGFR 等位基因的扩增和双特异性磷酸酶 4 (DUSP4) 的缺失，这两种情况之前都有报道。此外，我们确定了突变 EGFR 肿瘤中染色体臂 16p 片段的新扩增，对应于高尔基体相关、Gamma Adaptin Ear Containing、ARF 结合蛋白 2 (GGA2) 的表达增加，该蛋白在蛋白质运输和分类中起作用。我们发现 GGA2 与 EGFR 相互作用，在配体刺激后增加 EGFR 蛋白水平并改变 EGFR 降解。此外，我们表明 GGA2 的过表达增强了 EGFR 介导的转化，而 GGA2 敲低降低了 EGFR 突变体 LUAD 的集落和肿瘤形成能力。结论：这些数据表明 LUAD 肿瘤中 GGA2 的过表达导致 EGFR 蛋白的积累和 EGFR 信号传导增加，这有助于推动肿瘤进展。因此，GGA2 在 LUAD 开发过程中与 EGFR 发挥协同作用，并且是 LUAD 中基于组合策略的潜在治疗靶点。这些数据表明，LUAD 肿瘤中 GGA2 的过表达导致 EGFR 蛋白的积累和 EGFR 信号传导增加，这有助于推动肿瘤进展。因此，GGA2 在 LUAD 开发过程中与 EGFR 发挥协同作用，并且是 LUAD 中基于组合的策略的潜在治疗靶点。这些数据表明，LUAD 肿瘤中 GGA2 的过表达导致 EGFR 蛋白的积累和 EGFR 信号传导增加，这有助于推动肿瘤进展。因此，GGA2 在 LUAD 开发过程中与 EGFR 发挥协同作用，并且是 LUAD 中基于组合的策略的潜在治疗靶点。