PI3K/AKT inhibition induces compensatory activation of the MET/STAT3 pathway in non‑small cell lung cancer

Bian,Chunan; Liu,Zonghang; Li,Dakou; Zhen,Lifeng

doi:10.3892/ol.2018.8587

PI3K/AKT inhibition induces compensatory activation of the MET/STAT3 pathway in non‑small cell lung cancer

Authors:
- Chunan Bian
- Zonghang Liu
- Dakou Li
- Lifeng Zhen
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Affiliations: Department of Cardiothoracic Surgery, Nanjing Jiangbei People's Hospital, Nantong University, Nanjing, Jiangsu 210048, P.R. China
Published online on: April 26, 2018 https://doi.org/10.3892/ol.2018.8587
Pages: 9655-9662
Copyright: © Bian et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Constitutive activation of the phosphoinositide 3‑kinase (PI3K)/AKT signaling pathway is evident in a diverse array of human cancer types, and targeting the pathway is an attractive therapeutic approach. However, pre‑clinical and clinical studies have demonstrated that the antitumor efficacy of a number of inhibitors of the PI3K/AKT pathway is poor, and the underlying mechanisms are not completely clear. In the present study, activation of MET proto‑oncogene (MET)/signal transducer and activator of transcription 3 (STAT3) signaling was demonstrated during PI3K/AKT inhibition. Western blotting showed that the pharmacological or genetic inhibition of PI3K/AKT signaling triggered compensatory activation of STAT3 and upregulation of the expression of its downstream genes. The results from RTK array analysis and western blotting demonstrated that the hyperactivated STAT3 signaling was demonstrated to be mediated by the activation of MET. In addition, PI3K/AKT inhibition suppressed tumor growth more effectively when combined with inhibitors targeting MET/STAT3 signaling by detecting apoptosis and colony formation. These results were further confirmed in a nude mouse model. Thus, our results highlight a compensatory survival mechanism via the MET/STAT3 signaling pathway after PI3K/AKT signaling inhibition in non‑small cell lung cancer.

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