USP21-EGFR-Lyn Axis Drives NSCLC Progression and Therapeutic Potential of USP21 Inhibition

Non-small cell lung cancer (NSCLC) is a highly aggressive malignancy frequently driven by oncogenic mutations in the epidermal growth factor receptor (EGFR). Although EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have shown clinical efficacy, challenges such as limited response duration and intrinsic mechanisms—such as EGFR amplification—can affect therapeutic outcomes. This study investigates the role of the USP21–EGFR–Lyn axis in NSCLC progression, identifying USP21 as a key regulator of EGFR and Lyn stability. Gene Set Enrichment Analysis (GSEA) of NSCLC patient datasets revealed a strong correlation between USP21 overexpression and poor prognosis. Functional studies using USP21-knockout (USP21-KO) lung cancer cell lines demonstrated reduced proliferation, migration, colony formation, and tumor spheroid growth. Mechanistically, USP21 interacts with EGFR and Lyn, preventing their ubiquitination and degradation, thereby sustaining oncogenic signaling. In vivo, USP21 depletion significantly suppressed tumor growth in xenograft models. Additionally, pharmacological inhibition of USP21 with BAY-805 effectively reduced EGF-induced tumor spheroid formation, highlighting its therapeutic potential. Collectively, these findings position USP21 as a promising target for NSCLC treatment and offer a potential approach to complement existing EGFR-targeted therapies.