{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T12:35:57Z","timestamp":1789043757447,"version":"build-2803163510"},"reference-count":97,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T00:00:00Z","timestamp":1751241600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministero della Salute"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Epidermal growth factor receptor (EGFR) mutations occur in approximately 10\u201320% of Caucasian and up to 50% of Asian patients with oncogene-addicted non-small cell lung cancer (NSCLC). Most frequently, alterations include exon 19 deletions and exon 21 L858R mutations, which confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs). In the last decade, the third-generation EGFR-TKI osimertinib has represented the first-line standard of care for EGFR-mutant NSCLC. However, the development of acquired mechanisms of resistance significantly impacts long-term outcomes and represents a major therapeutic challenge. The mesenchymal\u2013epithelial transition (MET) gene amplification and MET protein overexpression have emerged as prominent EGFR-independent (off-target) resistance mechanisms, detected in approximately 25% of osimertinib-resistant NSCLC. Noteworthy, variability in diagnostic thresholds, which differ between fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) platforms, complicates its interpretation and clinical applicability. To address MET-driven resistance, several therapeutic strategies have been explored, including MET-TKIs, antibody\u2013drug conjugates (ADCs), and bispecific monoclonal antibodies, and dual EGFR\/MET inhibition has emerged as the most promising strategy. In this context, the bispecific EGFR\/MET antibody amivantamab has demonstrated encouraging efficacy, regardless of MET alterations. Furthermore, the combination of the ADC telisotuzumab vedotin and osimertinib has been associated with activity in EGFR-mutant, c-MET protein-overexpressing, osimertinib-resistant NSCLC. Of note, several novel agents and combinations are currently under clinical development. The success of these targeted approaches relies on tissue re-biopsy at progression and accurate molecular profiling. Yet, tumor heterogeneity and procedural limitations may challenge the feasibility of re-biopsy, making biomarker-agnostic strategies viable alternatives.<\/jats:p>","DOI":"10.3390\/genes16070772","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T10:45:08Z","timestamp":1751366708000},"page":"772","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Management of MET-Driven Resistance to Osimertinib in EGFR-Mutant Non-Small Cell Lung Cancer"],"prefix":"10.3390","volume":"16","author":[{"given":"Panagiotis Agisilaos","family":"Angelopoulos","sequence":"first","affiliation":[{"name":"Department of Oncology and Haemato-Oncology, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7575-3870","authenticated-orcid":false,"given":"Antonio","family":"Passaro","sequence":"additional","affiliation":[{"name":"Division of Thoracic Oncology, European Institute of Oncology, IRCCS, 20141 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1333-6622","authenticated-orcid":false,"given":"Ilaria","family":"Attili","sequence":"additional","affiliation":[{"name":"Division of Thoracic Oncology, European Institute of Oncology, IRCCS, 20141 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4341-003X","authenticated-orcid":false,"given":"Pamela","family":"Trillo Aliaga","sequence":"additional","affiliation":[{"name":"Division of Thoracic Oncology, European Institute of Oncology, IRCCS, 20141 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Corvaja","sequence":"additional","affiliation":[{"name":"Division of Thoracic Oncology, European Institute of Oncology, IRCCS, 20141 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3742-9962","authenticated-orcid":false,"given":"Gianluca","family":"Spitaleri","sequence":"additional","affiliation":[{"name":"Division of Thoracic Oncology, European Institute of Oncology, IRCCS, 20141 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Battaiotto","sequence":"additional","affiliation":[{"name":"Department of Oncology and Haemato-Oncology, University of Milan, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5286-7285","authenticated-orcid":false,"given":"Ester","family":"Del Signore","sequence":"additional","affiliation":[{"name":"Division of Thoracic Oncology, European Institute of Oncology, IRCCS, 20141 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1781-2518","authenticated-orcid":false,"given":"Giuseppe","family":"Curigliano","sequence":"additional","affiliation":[{"name":"Department of Oncology and Haemato-Oncology, University of Milan, 20122 Milan, Italy"},{"name":"Division of Early Drug Development, European Institute of Oncology, IRCCS, 20141 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo","family":"de Marinis","sequence":"additional","affiliation":[{"name":"Division of Thoracic Oncology, European Institute of Oncology, IRCCS, 20141 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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