{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T15:39:14Z","timestamp":1786117154960,"version":"build-2736575974"},"reference-count":49,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"DOI":"10.13039\/501100014188","name":"Ministry of Science and ICT, South Korea","doi-asserted-by":"publisher","award":["No. RS-2020-NR049559"],"award-info":[{"award-number":["No. RS-2020-NR049559"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Integr Cancer Ther"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      First-generation EGFR-TKIs in NSCLC frequently lose efficacy as a result of the secondary EGFR-T790M mutation and a \u201cpersistent-STAT3\u201d prosurvival pathway that sustains STAT3\u2013survivin signaling in the face of EGFR inhibition. Preclinical evidence demonstrates that phytochemicals in the JI017 herbal formulation (2:1:1,\n                      <jats:italic toggle=\"yes\">Angelica gigas<\/jats:italic>\n                      : processed\n                      <jats:italic toggle=\"yes\">Aconitum carmichaeli<\/jats:italic>\n                      :\n                      <jats:italic toggle=\"yes\">Zingiber officinale<\/jats:italic>\n                      ) can reinstate erlotinib sensitivity in T790M-positive NSCLC, and relevant molecular mechanisms have been examined.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Anti-proliferative activities were evaluated in A549 (EGFR-WT), HCC827 (EGFR \u039419), and H1975 (EGFR L858R\/T790M) cells utilizing MTT assays, colony formation, and Annexin V\/7-AAD flow cytometry. Mechanistic analyses included immunoblotting for p-EGFR (Tyr1068\/1173), p-JAK2, p-STAT3 (Tyr705), PARP, Bcl-2, survivin, and AXL, complemented by RT-qPCR for BIRC5 and AXL transcripts. Drug interaction effects were determined using the Chou\u2013Talalay combination index (CompuSyn). Anti-tumor efficacy was assessed in H1975 xenografts treated for 14 days with vehicle, JI017, erlotinib, or combination therapy; tumors underwent H&amp;E staining and IHC for p-STAT3, survivin, and Ki-67.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>JI017 inhibited proliferation in all NSCLC cell lines tested, showing greatest effectiveness in H1975, where it triggered PARP cleavage and suppression of Bcl-2 and survivin expression. In H1975, co-treatment with JI017 and erlotinib led to synergistic growth inhibition, eradicated colony growth, and significantly elevated apoptotic cell populations compared to single treatments. While erlotinib alone reduced p-EGFR and p-JAK2, it left p-STAT3 largely unaltered, reflecting persistent-STAT3 activity. The combination regimen abrogated p-STAT3, further lowered p-EGFR and p-JAK2 levels, diminished BIRC5 mRNA, and decreased both AXL protein and transcript levels. In vivo, the drug combination achieved sustained tumor stasis relative to controls or monotherapy; combination group tumors displayed widespread necrosis and substantial decreases in p-STAT3, survivin, and Ki-67.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These data support the suppression of STAT3\u2013survivin as the primary mechanism by which JI017 sensitizes EGFR-T790M models to erlotinib. The consistent down-regulation of AXL indicates the inhibition of an AXL-mediated bypass that may maintain STAT3 signaling during EGFR blockade, although causality has yet to be confirmed. The marked in-vivo tumor inhibition without observable toxicity underscores the translational promise as a low-toxicity therapeutic adjunct.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>JI017 restores erlotinib sensitivity in EGFR-T790M NSCLC by inhibiting STAT3\u2013survivin signaling and possibly reducing AXL-mediated resistance, resulting in durable antitumor effects both in vitro and in vivo. Additional preclinical studies and early-phase clinical assessment of JI017 in combination with erlotinib are justified.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/15347354261475694","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T11:06:21Z","timestamp":1785841581000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["JI017 Sensitizes EGFR-T790M NSCLC to Erlotinib by Extinguishing the STAT3\u2013Survivin Axis"],"prefix":"10.1177","volume":"25","author":[{"given":"Daeun","family":"Kim","sequence":"first","affiliation":[{"name":"Kyung Hee University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young-Ha","family":"Kim","sequence":"additional","affiliation":[{"name":"Kyung Hee University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaeun","family":"Choi","sequence":"additional","affiliation":[{"name":"Kyung Hee 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