Essential role for STAT3/FOXM1/ATG7 signaling-dependent autophagy in resistance to Icotinib

Lyu，Xin1; Zeng，Lizhong1; Shi，Jie1; Ming，Zongjuan1; Li，Wei1; Liu，Boxuan1; Chen，Yang1; Yuan，Bo1; Sun，Ruiying1; Yuan，Jingyan1; Zhao，Nannan1; Yang，Xia1; Chen，Guoan2; Yang，Shuanying1

2022-12-01

10.1186/s13046-022-02390-6

Journal of Experimental and Clinical Cancer Research   影响因子和分区

1756-9966

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. Graphical abstract: [Figure not available: see fulltext.]

ATG7 Autophagy Icotinib Non-small cell lung cancer Resistance

SCI

英语

其他

National Demonstration Center for Experimental Light Chemistry Engineering Education, Shaanxi University of Science and Technology[2017JM8159];Shaanxi University of Science and Technology[2017JM8159];National Natural Science Foundation of China[81672300];

Oncology

Oncology

WOS:000809567900001

BMC

CLINICAL MEDICINE

2-s2.0-85131793582

Scopus

1.Department of Pulmonary and Critical Care Medicine,Second Affiliated Hospital,Xi’an Jiaotong University,Xi’an,No. 157, Xiwu Road, Xincheng District, Shaanxi,710004,China
2.School of Medicine,Southern University of Science and Technology,Shenzhen,No. 1088, Xueyuan Road, Nanshan District, Guangdong,518055,China

Lyu，Xin,Zeng，Lizhong,Shi，Jie,et al. Essential role for STAT3/FOXM1/ATG7 signaling-dependent autophagy in resistance to Icotinib[J]. Journal of Experimental and Clinical Cancer Research,2022,41(1).

Lyu，Xin.,Zeng，Lizhong.,Shi，Jie.,Ming，Zongjuan.,Li，Wei.,...&Yang，Shuanying.(2022).Essential role for STAT3/FOXM1/ATG7 signaling-dependent autophagy in resistance to Icotinib.Journal of Experimental and Clinical Cancer Research,41(1).

Lyu，Xin,et al."Essential role for STAT3/FOXM1/ATG7 signaling-dependent autophagy in resistance to Icotinib".Journal of Experimental and Clinical Cancer Research 41.1(2022).