{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T17:10:14Z","timestamp":1790097014465,"version":"4.0.1"},"reference-count":57,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Touro College","award":["PRDG_2024_BHS"],"award-info":[{"award-number":["PRDG_2024_BHS"]}],"id":[{"id":"https:\/\/ror.org\/05hwfvk38","id-type":"ROR","asserted-by":"crossref"}]},{"award":["PRDG_2024_BHS"],"award-info":[{"award-number":["PRDG_2024_BHS"]}],"id":[{"id":"https:\/\/ror.org\/05hwfvk38","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors remains the principal barrier to durable responses in non-small cell lung cancer (NSCLC), yet how the molecular interaction networks underlying this resistance reorganize over time is poorly understood. We reasoned that a systems-level signature of resistance should be visible in the way protein interaction networks remodel under sustained drug exposure, and therefore applied time-resolved network analysis to isogenic gefitinib-sensitive PC9 and gefitinib-resistant PC9R cells across 24 h of gefitinib treatment, computing network entropy and centrality measures for temporal protein interaction networks and interrogating co-expression-augmented networks for candidate resistance-associated bottleneck proteins. Network entropy rose in both phenotypes, indicating that entropic remodeling is a general response to EGFR pathway perturbation rather than a signature of resistance. In contrast, eigenvector entropy was higher in resistant cells at the earliest post-treatment time point, and resistant cells preserved giant-component connectivity and small-world topology early before fragmenting later. Temporal centrality analysis nominated BIRC3 as a resistant-cell-associated high-centrality node at 24 h, and co-expression analysis identified delta-catenin (CTNND1) as a high-betweenness bottleneck in the PC9R network, topologically bridging EGFR, VAV3, HIF3A, and NOTCH2. These findings nominate early post-treatment eigenvector entropy and a CTNND1-centered, EGFR-enriched subnetwork as candidate resistance-associated features that require validation in independent datasets and functional models.<\/jats:p>","DOI":"10.3390\/ijms27188409","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:32:12Z","timestamp":1790083932000},"page":"8409","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Time-Resolved Network Entropy Analysis Identifies a CTNND1\u2013VAV3 Subnetwork in Gefitinib-Resistant NSCLC"],"prefix":"10.3390","volume":"27","author":[{"given":"Dimitra C.","family":"Tsakona","sequence":"first","affiliation":[{"name":"Inter-Faculty Program on Networks and Complexity, Aristotle University of Thessaloniki, 54124 Thessaloniki, Macedonia, Greece"},{"name":"Department of Biology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Macedonia, Greece"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Nikolaos A.","family":"Papanikolaou","sequence":"additional","affiliation":[{"name":"Department of Basic Sciences, Touro College of Osteopathic Medicine, Touro University, New York, NY 10027, USA"},{"name":"Laboratory of Biological Chemistry, Aristotle University of Thessaloniki School of Medicine, 54124 Thessaloniki, Macedonia, Greece"},{"name":"Akesis Synergy Med, 49 Arkadiou Str., 56121 Thessaloniki, Macedonia, Greece"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global cancer statistics 2020: GLOBOCAN estimates","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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