The E3 ubiquitin ligase NEDD4 mediates EGFR-TKI acquired resistance in non-small cell lung cancer

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) have been employed as the first-line treatment for lung adenocarcinoma patients with advanced EGFR-positive mutations, especially in patients with EGFR exon 21 L858R mutation or an exon 19 deletion. However, almost all patients inevitably develop acquired resistance to EGFR-TKI after 1 to 2 years, due to EGFR gene secondary mutations, MET gene amplification, KRAS mutation, loss of phosphatase and tensin homolog (PTEN), and other mechanisms. Therefore, the EGFR-TKI acquired resistance becomes a bottleneck of continuation for EGFR-TKI therapy in clinic. The neuronally expressed developmentally downregulated 4 (NEDD4), an E3 ubiquitin ligase, has been demonstrated to play an important role in the development and progression of human cancers. NEDD4 is frequently overexpressed in non-small cell lung cancer carcinomas (NSCLC) and is implicated in the regulation of ubiquitination of Ras and PTEN. NEDD4 overexpression promoted cellular transformation and induced EGFR-TKI acquired resistance in NSCLC. In this review, we will describe how NEDD4 regulates EGFR-TKI acquired resistance in NSCLC, and further discuss its mechanism, including PTEN poly-ubiquitination, Ras signaling activation, and EMT conversion. Therefore, targeting NEDD4 could be a potential therapeutic strategy for NSCLC after EGFR-TKI acquired resistance.