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KMID : 0043320230460110907
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Archives of Pharmacal Research
2023 Volume.46 No. 11 p.907 ~ p.938
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Role of monocarboxylate transporter I/lactate dehydrogenase B-mediated lactate recycling in tamoxifen-resistant breast cancer cells
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Choi Min-Chang
Kim Sang-Kyum
Choi Young-Jae
Choi Yong-June
Kim Sun-Tae
Jegal Kyung-Hwan
Lim Sung-Chul
Kang Keon-Wook
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Abstract
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Gefi tinib, as the fi rst-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has achieved greatadvances in the treatment of non-small cell lung cancer (NSCLC), but drug resistance will inevitably occur. Therefore,exploring the resistance mechanism of gefi tinib and developing new combination treatment strategies are of great importance.
In our study, the results showed that selumetinib (AZD6244) synergistically inhibited the proliferation of NSCLCwith gefi tinib. Selumetinib also enhanced gefi tinib-induced apoptosis and migration inhibition ability in gefi tinib-resistantlung cancer cell lines. Subsequently, the negative regulation between MIG6 and STAT3 was observed and verifi ed throughthe STRING database and western blotting assays. Sustained activation of STAT3 was signifi cantly downregulated whenco-treatment with selumetinib in gefi tinib-resistant cells. However, the downregulation of p-STAT3, resulting from thecombination of selumetinib and gefi tinib was counteracted by the deletion of MIG6, suggesting that selumetinib enhancedgefi tinib sensitivity by regulating MIG6/STAT3 in NSCLC. In contrast, p-STAT3 was further inhibited after treatment withgefi tinib and selumetinib when MIG6 was overexpressed. Furthermore, the combined administration of selumetinib andgefi tinib eff ectively promoted the sensitivity of lung cancer xenografts to gefi tinib in vivo, and the tumor inhibition ratereached 81.49%, while the tumor inhibition rate of the gefi tinib monotherapy group was only 31.95%. Overall, MIG6/STAT3negative regulation plays an important role in the sustained activation of STAT3 and the resistance to EGFR-TKIs. Our studyalso suggests that EGFR-TKIs combined with MEK1/2 inhibitors, such as selumetinib, may be benefi cial to those NSCLCpatients who develop a primary or acquired resistance to EGFR-TKIs, providing theoretical support for combining TKIs andselumetinib 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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