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Author Notes:

Xingming Deng, Division of Cancer Biology, Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA. Phone: (404) 778-3398; xdeng4@emory.edu.

Conception and design: X. Deng, R. Li; Development of methodology: X. Deng, R. Li, Z. Hu; Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): R. Li, Z. Hu, G. L. Sica, Z. Chen; Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): X. Deng, R. Li, Z. Hu; Writing, review, and/or revision of the manuscript: X. Deng, R. Li, S.Y. Sun, Z. Chen, T.K. Owonikoko, G. L. Sica, S. S. Ramalingam, W. J. Curran, F. R. Khuri; Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): R. Li, X. Deng, W. J. Curran, F. R. Khuri, S.Y. Sun; Study supervision: X. Deng.

We thank Anthea Hammond for professional editing of the manuscript.

The authors disclose no potential conflicts of interest


Research Funding:

This work was supported by NCI, National Institutes of Health Grants R01CA112183 (X. Deng) and R01CA136534 (X. Deng); and by Flight Attendant Medical Research Institute Clinical Innovator Award (X. Deng).


  • Science & Technology
  • Life Sciences & Biomedicine
  • Oncology

Niclosamide Overcomes Acquired Resistance to Erlotinib through Suppression of STAT3 in Non-Small Cell Lung Cancer

Journal Title:

Molecular Cancer Therapeutics


Volume 12, Number 10


, Pages 2200-2212

Type of Work:

Article | Post-print: After Peer Review


The emergence of resistance to EGF receptor (EGFR) inhibitor therapy is a major clinical problem for patients with non-small cell lung cancer (NSCLC). The mechanisms underlying tumor resistance to inhibitors of the kinase activity of EGFR are not fully understood. Here, we found that inhibition of EGFR by erlotinib induces STAT3 phosphorylation at Tyr705 in association with increased Bcl2/Bcl-XL at both mRNA and protein levels in various human lung cancer cells. PTPMeg2 is a physiologic STAT3 phosphatase that can directly dephosphorylate STAT3 at the Tyr705 site. Intriguingly, treatment of cells with erlotinib results in downregulation of PTPMeg2 without activation of STAT3 kinases [i.e., Janusactivated kinase (JAK2) or c-Src], suggesting that erlotinib-enhanced phosphorylation of STAT3 may occur, at least in part, from suppression of PTPMeg2 expression. Because elevated levels of phosphorylated STAT3 (pSTAT3), Bcl2, and Bcl-XL were observed in erlotinib-resistant lung cancer (HCC827/ER) cells as compared with erlotinib-sensitive parental HCC827 cells, we postulate that the erlotinib-activated STAT3/Bcl2/Bcl-XL survival pathway may contribute to acquired resistance to erlotinib. Both blockage of Tyr705 phosphorylation of STAT3 by niclosamide and depletion of STAT3 by RNA interference in HCC827/ER cells reverse erlotinib resistance. Niclosamide in combination with erlotinib potently represses erlotinib-resistant lung cancer xenografts in association with increased apoptosis in tumor tissues, suggesting that niclosamide can restore sensitivity to erlotinib. These findings uncover a novel mechanism of erlotinib resistance and provide a novel approach to overcome resistance by blocking the STAT3/Bcl2/Bcl-XL survival signaling pathway in human lung cancer.

Copyright information:

© 2013 AACR.

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