CTNND1 (p120-Catenin; Catenin Delta-1), VAV3, and Network Entropy as Candidate Biomarkers of Gefitinib Resistance in Non-Small Cell Lung Cancer

Acquired resistance to EGFR tyrosine kinase inhibitors remains a principal barrier to durable remission in non-small cell lung cancer (NSCLC). Using a time-resolved protein interaction network analysis of isogenic Gefitinib-sensitive and resistant NSCLC cells, we show that network entropy increases progressively under drug treatment in both phenotypes, while small-world topology is lost, consistent with Gefitinib's dismantling of EGFR-centered signaling hubs. Eigenvector entropy alone distinguished the resistant phenotype at baseline, reflecting a pre-established, robustly buffered network state. Co-expression network analysis revealed a resistance-specific subnetwork in which delta-catenin (CTNND1) serves as the dominant topological bridge between EGFR, VAV3, HIF3A, and NOTCH2, four nodes independently linked to chemoresistance but not previously connected within a single regulatory network. We propose that HIF1α-driven induction of CTNND1, EGFR-mediated positive feedback, and VAV3-dependent Rho-GTPase activation cooperate to drive actin cytoskeletal remodeling and phenotypic switching. BIRC3 emerged as an independent late-stage apoptotic block exclusive to resistant cells. These findings nominate CTNND1 and VAV3 as candidate co-targets and eigenvector entropy as a systems-level biomarker of Gefitinib resistance.