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Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) remains a major challenge in non-small cell lung cancer (NSCLC) treatment. Although ascomycin (FK520) has demonstrated some antitumor activity, its potential in overcoming osimertinib resistance has not been fully characterized.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Cell viability and proliferation were assessed using the Cell Counting Kit 8 (CCK8) and colony formation assays, respectively, following treatment with ascomycin, osimertinib, or interleukin (IL)-6 for 48 h. Flow cytometry was employed to characterize cell cycle distribution and apoptotic rates. To identify key regulatory pathways, transcriptomic profiling was performed via RNA sequencing. The expression of relevant molecular targets was quantified using western blotting, and quantitative PCR (qPCR). Finally, the chemosensitizing effect of ascomycin was validated in vivousing established animal models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Ascomycin were observed to significantly enhanced the antiproliferative effects of osimertinib in EGFR-TKI-resistant lung cancer cells. Further analysis indicated that such effects may be mediated, at least in part, by modulating the interleukin-6\/signal transducer and activator of transcription 3 (IL-6\/STAT3) signaling pathway and promoting tumor cell apoptosis. Consistent with\n                      <jats:italic>in vitro<\/jats:italic>\n                      results, combined ascomycin and osimertinib treatment generated greater antitumor efficacy than either agent alone in osimertinib-resistant NSCLC xenograft models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Ascomycin may be an effective adjuvant in enhancing osimertinib therapeutic activity and overcoming acquired EGFR-TKI resistance, thereby providing a promising combination strategy for treating resistant NSCLC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1867321","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T04:37:51Z","timestamp":1787114271000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Ascomycin enhances 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