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KMID : 0043320230460110924
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Archives of Pharmacal Research
2023 Volume.46 No. 11 p.924 ~ p.938
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Selumetinib overcomes gefi tinib primary and acquired resistance by regulating MIG6/STAT3 in NSCLC
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Xiaoping Song
Lina Wang
Wei Tang
Luyao Yuan
Qingchao Liu
Jing Li
Daidi Fan
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Abstract
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Geftinib, as the frst-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has achieved great
advances in the treatment of non-small cell lung cancer (NSCLC), but drug resistance will inevitably occur. Therefore,
exploring the resistance mechanism of geftinib and developing new combination treatment strategies are of great importance. In our study, the results showed that selumetinib (AZD6244) synergistically inhibited the proliferation of NSCLC
with geftinib. Selumetinib also enhanced geftinib-induced apoptosis and migration inhibition ability in geftinib-resistant
lung cancer cell lines. Subsequently, the negative regulation between MIG6 and STAT3 was observed and verifed through
the STRING database and western blotting assays. Sustained activation of STAT3 was signifcantly downregulated when
co-treatment with selumetinib in geftinib-resistant cells. However, the downregulation of p-STAT3, resulting from the
combination of selumetinib and geftinib was counteracted by the deletion of MIG6, suggesting that selumetinib enhanced
geftinib sensitivity by regulating MIG6/STAT3 in NSCLC. In contrast, p-STAT3 was further inhibited after treatment with
geftinib and selumetinib when MIG6 was overexpressed. Furthermore, the combined administration of selumetinib and
geftinib efectively promoted the sensitivity of lung cancer xenografts to geftinib in vivo, and the tumor inhibition rate
reached 81.49%, while the tumor inhibition rate of the geftinib monotherapy group was only 31.95%. Overall, MIG6/STAT3
negative regulation plays an important role in the sustained activation of STAT3 and the resistance to EGFR-TKIs. Our study also suggests that EGFR-TKIs combined with MEK1/2 inhibitors, such as selumetinib, may be benefcial to those NSCLC patients who develop a primary or acquired resistance to EGFR-TKIs, providing theoretical support for combining TKIs and selumetinib in clinical cancer treatment.
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KEYWORD
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Gefi tinib, Selumetinib, Drug Resistance, MIG6/STAT3, NSCLC
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