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JI017 Sensitizes EGFR-T790M NSCLC to Erlotinib by Extinguishing the STAT3–Survivin Axis
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DOI：10.1177/15347354261475694.png)
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Abstract
En 中文
<jats:sec>
<jats:title>Introduction</jats:title>
<jats:p>
First-generation EGFR-TKIs in NSCLC frequently lose efficacy as a result of the secondary EGFR-T790M mutation and a “persistent-STAT3” prosurvival pathway that sustains STAT3–survivin signaling in the face of EGFR inhibition. Preclinical evidence demonstrates that phytochemicals in the JI017 herbal formulation (2:1:1,
<jats:italic toggle="yes">Angelica gigas</jats:italic>
: processed
<jats:italic toggle="yes">Aconitum carmichaeli</jats:italic>
:
<jats:italic toggle="yes">Zingiber officinale</jats:italic>
) can reinstate erlotinib sensitivity in T790M-positive NSCLC, and relevant molecular mechanisms have been examined.
</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Methods</jats:title>
<jats:p>Anti-proliferative activities were evaluated in A549 (EGFR-WT), HCC827 (EGFR Δ19), 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–Talalay 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&E staining and IHC for p-STAT3, survivin, and Ki-67.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Results</jats:title>
<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>
</jats:sec>
<jats:sec>
<jats:title>Discussion</jats:title>
<jats:p>These data support the suppression of STAT3–survivin 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>
</jats:sec>
<jats:sec>
<jats:title>Conclusions</jats:title>
<jats:p>JI017 restores erlotinib sensitivity in EGFR-T790M NSCLC by inhibiting STAT3–survivin 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>
</jats:sec>
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