Integrative Genomic Analyses Identifies GGA2 as a Cooperative Driver of EGFR-Mediated Lung Tumorigenesis.

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.

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