Niclosamide Overcomes Acquired Resistance to Erlotinib through Suppression of STAT3 in Non–Small Cell Lung Cancer
Authors: Gabriel L Sica
Shi-Yong Sun
Rui Li
Zhuo G Chen
Suresh S Ramalingam
Walter J Curran
Xingming Deng
Taofeek K Owonikoko
Zhongliang Hu
Fadlo R Khuri
Journal: Molecular Cancer Therapeutics (2013)
Discipline: CLINICAL MEDICINE
Keywords: EGFR inhibitor therapy; resistance; NSCLC; STAT3 phosphorylation; Bcl2
Affiliations: Corresponding Author: 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. .

Abstract:  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., Janus-activated 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. 

Retracted: No

PubPeer comments:
 Figure 6B. Much more similar than you would expect, yet the xenografts are derived from different cell lines. https: imgur.com WbATblH , 
 We submitted u201cMCTu201d manuscript (Feb., 2013) ahead of u201cPLOS ONEu201d manuscript (May, 2013). I think that images in Figure 6B in MCT paper should be right. Images in Figure 5B in PLOSE ONE paper should have problems. When I submitted u201cPLOS ONEu201d manuscript, I did not compared all Figures with u201cMCTu201d manuscript that Dr. Rui Li provided. Sorry, I did not catch this mistake between these two papers from Dr. Rui Li (She is first author for both papers). The first author Dr. Rui Li already left my lab and returned China since 2015. After she left, I communicated her via her g-mail (the only contact information she left) but I never received any response from her. Thus, I suggest that we can re-do Figure 5B experiments for u201cPLOSE ONEu201d paper, and provide accurate images for Figure 5B of u201cPLOSE ONEu201d paper. Thank you for your good catching and valuable information. , 
 Images of Figure 6B in MCT paper is right, and do not need to do any correction. We did correction for PloS One paper. The corrected image of Figure 5B (Upper panel) for  PloS One is attached as below. We also contacted  PLoS One for this correction. This correction does not change any conclusions made in the article. ![file] ,