AXIN1/MYC Axis Mediated the Osimertinib Resistance in EGFR Mutant Non-Small Cell Lung Cancer Cells

AXIN1/MYC Axis Mediated the Osimertinib Resistance in EGFR Mutant Non-Small Cell Lung Cancer Cells

Haoyue Yu,^1,2 Zhiguo Wang,^1,3 Yan Dong,² Li Li,¹ Xianming Fan,³ Nan Zheng,¹ ji Jiang,¹ Caiyu Lin,¹ Conghua Lu,¹ Kunlin Li¹ and Mingxia Feng¹

¹Department of Respiratory Disease, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, China
²Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
³Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, China

Osimertinib, a promising and approved third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is a standard strategy for EGFR-mutant non-small cell lung cancer (NSCLC) patients. However, developed resistance is unavoidable, which reduces its long-term effectiveness. In this study, RNA sequencing was performed to analyze differentially expressed genes (DEGs). The PrognoScan database and Gene Expression Profiling Interactive Analysis (GEPIA) were used to identify the key genes for clinical prognosis and gene correlation respectively. Protein expression was determined by western blot analysis. Cell viability assay and Ki67 staining were used to evaluate the effect of osimertinib on tumor cells. Finally, we screened out two hub genes, myelocytomatosis oncogene (Myc) and axis inhibition protein 1 (Axin1), upregulated in three osimertinib-resistant cell lines through RNA sequencing and bioinformatics analysis. Next, cell experiment confirmed that expression of C-MYC and AXIN1 were elevated in different EGFR mutant NSCLC cell lines with acquired resistance to osimertinib, compared with their corresponding parental cell lines. Furthermore, we demonstrated that AXIN1 upregulated the expression of C-MYC and mediated the acquired resistance of EGFR mutant NSCLC cells to osimertinib in vitro. In conclusion, AXIN1 affected the sensitivity of EGFR mutant NSCLC to osimertinib via regulating C-MYC expression in vitro. Targeting AXIN1/MYC signaling may be a potential new strategy for overcoming acquired resistance to osimertinib.

Key words —— AXIN1; EGFR; MYC; NSCLC; osimertinib

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Tohoku J. Exp. Med., 2024 April, 262(4), 269-276.

*These three authors contributed equally to this work.

Correspondence: Mingxia Feng, Department of Respiratory Disease, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road Yuzhong District, Chongqing 400042, China.

e-mail: fmx19810306@tmmu.edu.cn

Kunlin Li, Department of Respiratory Disease, Daping Hospital, Army Medical University (Third Military Medical University), 10 Changjiang Branch Road Yuzhong District, Chongqing 400042, China.

e-mail: li676@sina.com