J Cancer 2020; 11(19):5746-5757. doi:10.7150/jca.37417

Research Paper

Torin2 inhibits the EGFR-TKI resistant Non-Small Lung Cancer cell proliferation through negative feedback regulation of Akt/mTOR signaling

Yi Hu1#, Ji Zhang3#, Qun Liu2#, Mingyao Ke6#, Jiurong Li2, Wenhao Suo4, Weixi Guo5, Aiping Ma2✉

1. Department of Clinical Laboratory, The first affiliated hospital, School of Medicine, Xiamen University, Xiamen, China.
2. Department of Respiratory and Critical Medicine, The first affiliated hospital, School of Medicine, Xiamen University, Xiamen, China.
3. Wuxi Lung Transplant Center, Wuxi People's Hospital affiliated to Nanjing Medical University, Wuxi, China.
4. Department of Pathology, The first affiliated hospital, School of Medicine, Xiamen University, Xiamen, China.
5. Department of Thoracic Surgery, The first affiliated hospital, School of Medicine, Xiamen University, Xiamen, China.
6. Department of Respiratory and Critical Medicine, The secondary hospital of Xiamen Medicine school, Xiamen, China.
#These authors contributed equally to this work.

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Citation:
Hu Y, Zhang J, Liu Q, Ke M, Li J, Suo W, Guo W, Ma A. Torin2 inhibits the EGFR-TKI resistant Non-Small Lung Cancer cell proliferation through negative feedback regulation of Akt/mTOR signaling. J Cancer 2020; 11(19):5746-5757. doi:10.7150/jca.37417. Available from http://www.jcancer.org/v11p5746.htm

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Abstract

It is known that mammalian target of rapamycin (mTOR) signaling plays an important role in NSCLC cells proliferation. Torin2 is a second-generation ATP-competitive inhibitor which is selective for mTOR activity. In this study, we investigated whether torin2 was effective against lung cancer cells, especially EGFR-TKIs resistant NSCLC cells.

We found that torin2 dramatically inhibited EGFR-TKI resistant cells viability in vitro. In xenograft model, torin2 treatment significantly reduced the volume and weight of xenograft tumor in the erlotinib resistant PC9/E cells. Additionally, autophagy protein of phosphatidylethanolamine-modified microtubule-associated protein light-chain 3II/I (LC3II/I) increased in PC9/E after torin2 treatment. Torin2 blocked the level of phosphorylated S6 and the phosphorylation of Akt at both T308 and S473 sites compared with erlotinib treatment. Furthermore, TUNEL assay showed that apoptosis of tumor tissue increased significantly in the torin2 treatment group. Immunohistochemical analysis demonstrated that tumor angiogenesis was obviously inhibited by torin2 treatment in EGFR-TKI resistant group. Collectively, our results suggested that torin2 could inhibit the NSCLC cells proliferation by negative feedback regulation of Akt/mTOR signaling and inducing autophagy. This suggests that torin2 could be a novel therapeutic approach for EGFR-TKI resistant NSCLC.

Keywords: mTOR, Torin2, EGFR-TKI, Autophagy, Erlotinib