USP7 represents a therapeutic target for EGFR-driven and EGFR-TKI–resistance to EGFR mutations in lung cancer

Aberrant activation of the epidermal growth factor receptor (EGFR) pathway is a major oncogenic driver in non-small cell lung cancer (NSCLC), yet the mechanisms governing EGFR stability remain incompletely understood. Here, we identify the deubiquitinase USP7 as a master regulator of EGFR signaling and a therapeutic vulnerability in both EGFR-wild-type (EGFR ^WT ) and EGFR-mutant (EGFR ^Mut ) NSCLC. Transcriptomic analysis of 42 paired NSCLC specimens demonstrated that USP7 is frequently upregulated and is associated with poor prognosis, metastatic signatures, and activation of EGFR-related oncogenic pathways. Genetic ablation of USP7 markedly suppressed proliferation, migration, clonogenicity, three-dimensional spheroid growth, and tumorigenesis in NSG xenograft models. Mechanistically, USP7 directly interacted with and deubiquitinated both EGFR and c-Abl, thereby stabilizing these proteins and promoting assembly of the EGFR–c-Abl signaling complex. Consequently, USP7 enhanced downstream RAF–ERK and PI3K–AKT signaling, whereas restoration of USP7 expression rescued EGFR-dependent malignant phenotypes in USP7-deficient cells. Integrative transcriptomic and functional analyses further identified an EGFR–USP7–ABL1 signaling axis associated with aggressive NSCLC. Importantly, pharmacological inhibition of USP7 with P5091 destabilized EGFR and c-Abl, suppressed oncogenic signaling, and inhibited malignant phenotypes in both EGFR ^WT cells and clinically relevant EGFR ^Mut models, including H1975 (L858R/T790M/C797S) and HCC827 (exon 19 deletion). Collectively, our findings establish USP7 as a central stabilizer of the EGFR–c-Abl signaling hub and provide mechanistic and therapeutic evidence that targeting USP7 represents a promising strategy for treating EGFR-driven NSCLC, including tumors harboring EGFR mutations associated with resistance to EGFR tyrosine kinase inhibitors.