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Author Spotlight: A Selective Luciferase-Based Assay for Monitoring ATG4B 27 Activity in Cells
Published on: June 30, 2023
Essential role for STAT3/FOXM1/ATG7 signaling-dependent autophagy in resistance to Icotinib
Xin Lyu1, Lizhong Zeng1, Jie Shi1
1Department of Pulmonary and Critical Care Medicine, Second Affiliated Hospital, Xi'an Jiaotong University, No. 157, Xiwu Road, Xincheng District, Xi'an, 710004, Shaanxi, People's Republic of China.
Background:
The contribution of autophagy to cancer therapy resistance remains complex, mainly owing to the discrepancy of autophagy mechanisms in different therapy. However, the potential mechanisms of autophagy-mediated resistance to icotinib have yet to be elucidated.
Methods:
The effect of autophagy in icotinib resistance was examined using a series of in vitro and in vivo assays. The results above were further verified in biopsy specimens of lung cancer patients before and after icotinib or gefitinib treatment.
Results:
Icotinib increased ATG3, ATG5, and ATG7 expression, but without affecting Beclin-1, VPS34 and ATBG14 levels in icotinib-resistant lung cancer cells. Autophagy blockade by 3-MA or silencing Beclin-1 had no effects on resistance to icotinib. CQ effectively restored lung cancer cell sensitivity to icotinib in vitro and in vivo. Notably, aberrantly activated STAT3 and highly expressed FOXM1 were required for autophagy induced by icotinib, without the involvement of AMPK/mTOR pathway in this process. Alterations of STAT3 activity using genetic and/or pharmacological methods effectively affected FOXM1 and ATG7 levels increased by icotinib, with altering autophagy and icotinib-mediated apoptosis in resistant cells. Furthermore, silencing FOXM1 impaired up-regulated ATG7 induced by STAT3-CA and icotinib. STAT3/FOXM1 signalling blockade also reversed resistance to icotinib in vivo. Finally, we found a negative correlation between STAT3/FOXM1/ATG7 signalling activity and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) treatment efficacy in patients undergoing EGFR-TKIs treatment.
Conclusions:
Our findings support that STAT3/FOXM1/ATG7 signalling-induced autophagy is a novel mechanism of resistance to icotinib, and provide insights into potential clinical values of ATG7-dependent autophagy in icotinib treatment.
Insights
Autophagy, driven by STAT3/FOXM1/ATG7 signaling, promotes resistance to icotinib in lung cancer. Blocking this pathway restores sensitivity, offering potential therapeutic strategies for EGFR-TKI treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cellular Biology
Background:
- Autophagy's role in cancer therapy resistance is complex and not fully understood.
- Mechanisms of autophagy-mediated resistance to icotinib (a tyrosine kinase inhibitor) are largely unknown.
Purpose of the Study:
- To elucidate the mechanisms of autophagy-induced resistance to icotinib in lung cancer.
- To investigate the potential clinical implications of targeting autophagy in icotinib treatment.
Main Methods:
- In vitro and in vivo assays were used to examine autophagy's effect on icotinib resistance.
- Patient biopsy specimens before and after icotinib or gefitinib treatment were analyzed.
- Genetic and pharmacological methods were employed to modulate STAT3 and FOXM1 signaling pathways.
Main Results:
- Icotinib treatment upregulated ATG3, ATG5, and ATG7, but not Beclin-1 or VPS34, in resistant cells.
- STAT3 and FOXM1 activation were essential for icotinib-induced autophagy, independent of the AMPK/mTOR pathway.
- STAT3/FOXM1/ATG7 signaling blockade reversed icotinib resistance in vitro and in vivo.
- A negative correlation was observed between STAT3/FOXM1/ATG7 signaling activity and EGFR-TKI treatment efficacy in patients.
Conclusions:
- STAT3/FOXM1/ATG7 signaling-induced autophagy represents a novel mechanism of icotinib resistance in lung cancer.
- Targeting ATG7-dependent autophagy may offer a viable strategy to overcome icotinib resistance.
- These findings highlight potential clinical applications for modulating autophagy in EGFR-TKI therapy.
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