{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T13:28:45Z","timestamp":1786973325453,"version":"build-2736575974"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":68,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality worldwide. Tumors carrying activating epidermal growth factor receptor (EGFR) mutations initially respond to tyrosine kinase inhibitors (TKIs), with Osimertinib representing the current standard of care. However, acquired resistance inevitably develops, involving both genetic and non-genetic mechanisms, the latter playing a major role in sustaining cellular plasticity and promoting tumor aggressiveness. Here, we show that Osimertinib-resistant H1975 cells acquire a more aggressive phenotype than their parental (Par) counterparts, characterized by enhanced migratory behavior and transcriptional enrichment of BMI1 target genes, as well as mitotic defects and concomitant alterations in expression of mitotic cell-cycle pathways. Despite unchanged proliferation, resistant cells display increased mitotic activity and frequent cytokinetic defects, revealing a dependency on mitotic machinery and microtubule integrity, an Achilles\u2019 heel created by adaptive resistance. Functionally, BMI1 overexpression in Par cells recapitulates both resistance and enhanced migration, highlighting its central role in driving the resistant phenotype. Exploiting these vulnerabilities, Unesbulin (PTC596), a tubulin-binding agent with BMI1 inhibitory activity, triggers mitotic catastrophe, mechanistically induces apoptosis in vitro and drives regression of resistant xenografts in vivo. Our findings establish BMI1 as a key mediator of Osimertinib resistance and aggressiveness, uncovering a mutation-context-dependent mitotic vulnerability that can be therapeutically exploited, providing a rationale for targeting BMI1 and mitotic abnormalities to overcome resistance in T790M\/L858R backgrounds.<\/jats:p>","DOI":"10.1038\/s41419-026-08952-2","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T15:56:36Z","timestamp":1781106996000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dual actionability of BMI1 activation and mitotic vulnerability defines adaptive Osimertinib resistance in EGFR-mutant NSCLC"],"prefix":"10.1038","volume":"17","author":[{"given":"Paolo","family":"Armanetti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Cabrera San Millan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maddalena","family":"Di Nardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaella","family":"Mercatelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Cavallini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Crucitta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marzia","family":"Del Re","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Chiodi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3102-5150","authenticated-orcid":false,"given":"Ettore","family":"Mosca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Consiglio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Losito","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7701-6543","authenticated-orcid":false,"given":"Antonio","family":"Musio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Menichetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8478-7370","authenticated-orcid":false,"given":"Emilia","family":"Bramanti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Azhar","family":"Ali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4612-3105","authenticated-orcid":false,"given":"Elena","family":"Levantini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1866-5898","authenticated-orcid":false,"given":"Giorgia","family":"Maroni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"key":"8952_CR1","doi-asserted-by":"crossref","unstructured":"O\u2019Leary C, Gasper H, Sahin KB, Tang M, Kulasinghe A, Adams MN, et al. 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