Theranostics 2021; 11(2):824-840. doi:10.7150/thno.49600 This issue

Research Paper

A novel STAT3 inhibitor W2014-S regresses human non-small cell lung cancer xenografts and sensitizes EGFR-TKI acquired resistance

Qiyao Zheng1,2*, Hui Dong2*, Jianshan Mo1,2*, Yi Zhang2, Jie Huang3, Shumin Ouyang1,2, Shuo Shi1,2, Kai Zhu4, Xinming Qu4, Wenhao Hu2, Peiqing Liu1✉, Yuanxiang Wang2✉, Xiaolei Zhang1,2✉

1. Guangdong Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China
2. Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510006, China
3. Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital and Guangdong Academy of Medical Sciences, Guangzhou 510080, China
4. Innovation Practice Center, Changchun University of Chinese Medicine, Changchun, 130117, China
*These authors contributed equally.

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Citation:
Zheng Q, Dong H, Mo J, Zhang Y, Huang J, Ouyang S, Shi S, Zhu K, Qu X, Hu W, Liu P, Wang Y, Zhang X. A novel STAT3 inhibitor W2014-S regresses human non-small cell lung cancer xenografts and sensitizes EGFR-TKI acquired resistance. Theranostics 2021; 11(2):824-840. doi:10.7150/thno.49600. Available from https://www.thno.org/v11p0824.htm

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Abstract

Graphic abstract

Constitutive activation of signal transducer and activator of transcription 3 (STAT3) is a common feature in human non-small cell lung cancer (NSCLC). STAT3 plays an important role in cancer progression as a driver oncogene and acquired resistance of targeted therapies as an alternatively activated pathway. W2014-S with pharmacophore structure of imidazopyridine, which was firstly reported to be utilized in STAT3 inhibitor discovery, was screened out as a potent STAT3 inhibitor from a library of small molecules. The aim of this study is to investigate the antitumor activities and mechanisms of W2014-S in NSCLC and effect on epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) resistance in vitro and in vivo.

Methods: SPR analysis, Co-immunoprecipitation, confocal microscope imaging, and luciferase report gene assays were utilized to determine the mechanisms. Cell viability, colonial survival, wound healing, cell invasion assay, human cancer cell xenografts and PDX tumor xenografts were used to determine antitumor activities.

Results: W2014-S disrupted STAT3 dimerization and selectively inhibited aberrant STAT3 signaling in NSCLC cell line. W2014-S strongly suppressed proliferation, survival, migration and invasion of lung cancer cells with aberrant STAT3 activation and inhibited the growth of human NSCLC cell xenografts and PDX tumor xenografts in mouse model. Furthermore, W2014-S significantly sensitized resistant NSCLC cell line to gefitinib and erlotinib in vitro and enhances the anti-tumor effect of gefitinib in TKI-resistant lung cancer xenografts in vivo.

Conclusions: Our study has provided a novel STAT3 inhibitor with significant anti-tumor activities in NSCLC and suggests that combination of STAT3 inhibitor such as W2014-S with gefitinib could serve as a promising strategy to overcome EGFR-TKIs acquired resistance in NSCLC patients.

Keywords: STAT3 inhibitor, EGFR-TKI, acquired resistance, W2014-S, non-small cell lung cancer