{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T09:32:04Z","timestamp":1777627924389,"version":"3.51.4"},"reference-count":32,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T00:00:00Z","timestamp":1732492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007076","name":"Fondazione AIRC","doi-asserted-by":"publisher","award":["26237"],"award-info":[{"award-number":["26237"]}],"id":[{"id":"10.13039\/501100007076","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Oncogene-driven NSCLC is usually treated with targeted therapies using tyrosine kinase inhibitors (TKIs) to inhibit oncogene downstream signaling pathways, affecting tumor survival and proliferation. EGFR- and KRAS-mutant NSCLCs are the most represented subtypes, and they are treated in clinical practice with oncogene-targeting drugs in the first and second line, respectively. Unfortunately, the development of oncogene-independent resistant clones limits TKI efficacy. Here, we used non-oncogene addiction (NOA) as an innovative therapeutic strategy to target other essential proteins that support changes in tumor phenotype. Specifically, we tested, for the first time, a combination of inhibitors, namely ATR, involved in DNA damage response, and pyruvate dehydrogenase kinases (PDKs), involved in energy metabolism. Methods: Sensitive PC9 and the corresponding EGFR-TKI-resistant PC9\/OR, EGFR-mutant H1975, and KRAS-mutant A549 NSCLC cells, were treated with TKIs (osimertinib and selumetinib, respectively). In parallel, cells were exposed to two combination regimens: one using the TKI with an ATR inhibitor and the other one combining the two selected NOA inhibitors (ATR inhibitor, M4344; and PDK inhibitor, DCA). Results: The effect of these two combined approaches, compared to TKI alone, produced similar results in terms of cell proliferation, cell death, and migration. Thus, depending on tumor biology, selecting between the proposed therapeutic strategies will be different, to maximize tumor response. Conclusions: The major translational relevance of this study is to exploit new targets for the development of innovative and improved therapeutic strategies with NOA drugs, over combinations including target genes within the oncogene pathway, to overcome resistance to TKI therapies in patients with NSCLC who are oncogene-addicted.<\/jats:p>","DOI":"10.3390\/cancers16233941","type":"journal-article","created":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T08:38:24Z","timestamp":1732523904000},"page":"3941","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Combined Therapeutic Strategies Based on the Inhibition of Non-Oncogene Addiction to Improve Tumor Response in EGFR- and KRAS-Mutant Non-Small-Cell Lung Cancer"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-6511-8071","authenticated-orcid":false,"given":"Luisa","family":"Amato","sequence":"first","affiliation":[{"name":"Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8710-2971","authenticated-orcid":false,"given":"Daniela","family":"Omodei","sequence":"additional","affiliation":[{"name":"Institute of Biostructures and Bioimaging, National Research Council, 80145 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6540-0708","authenticated-orcid":false,"given":"Caterina","family":"De Rosa","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annalisa","family":"Ariano","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2109-1868","authenticated-orcid":false,"given":"Sara","family":"Capaldo","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4503-9117","authenticated-orcid":false,"given":"Camilla Carmela","family":"Tufano","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rossella","family":"Buono","sequence":"additional","affiliation":[{"name":"Institute of Biostructures and Bioimaging, National Research Council, 80145 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5422-4737","authenticated-orcid":false,"given":"Cristina","family":"Terlizzi","sequence":"additional","affiliation":[{"name":"Institute of Biostructures and Bioimaging, National Research Council, 80145 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Nardelli","sequence":"additional","affiliation":[{"name":"Institute of Biostructures and Bioimaging, National Research Council, 80145 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7323-4444","authenticated-orcid":false,"given":"Vitale","family":"Del Vecchio","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy"},{"name":"Department of Life Sciences, Health and Health Professions, Link Campus University, 00165 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3858-4529","authenticated-orcid":false,"given":"Rosanna","family":"Palumbo","sequence":"additional","affiliation":[{"name":"Institute of Biostructures and Bioimaging, National Research Council, 80145 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8713-2169","authenticated-orcid":false,"given":"Concetta","family":"Tuccillo","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Floriana","family":"Morgillo","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0302-8696","authenticated-orcid":false,"given":"Federica","family":"Papaccio","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Dentistry, \u201cScuola Medica Salernitana\u201d, University of Salerno, 84084 Baronissi, Italy"},{"name":"Clinical Pharmacology Unit, San Giovanni di Dio e Ruggi d\u2019Aragona University Hospital, 84131 Salerno, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Virginia","family":"Tirino","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5132-3593","authenticated-orcid":false,"given":"Francesca","family":"Iommelli","sequence":"additional","affiliation":[{"name":"Institute of Biostructures and Bioimaging, National Research Council, 80145 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3396-8099","authenticated-orcid":false,"given":"Carminia Maria","family":"Della Corte","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80131 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0430-5608","authenticated-orcid":false,"given":"Viviana","family":"De Rosa","sequence":"additional","affiliation":[{"name":"Institute of Biostructures and Bioimaging, National Research Council, 80145 Naples, 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