Research Papers:

This article has been corrected. Correction in: Oncotarget. 2019; 10:1603.

Small-molecule inhibition of STAT3 in radioresistant head and neck squamous cell carcinoma

Uddalak Bharadwaj _, T. Kris Eckols, Xuejun Xu, Moses M. Kasembeli, Yunyun Chen, Makoto Adachi, Yongcheng Song, Qianxing Mo, Stephen Y. Lai and David J. Tweardy

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Oncotarget. 2016; 7:26307-26330. https://doi.org/10.18632/oncotarget.8368

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Uddalak Bharadwaj1, T. Kris Eckols1, Xuejun Xu2, Moses M. Kasembeli1, Yunyun Chen3, Makoto Adachi3, Yongcheng Song4, Qianxing Mo5, Stephen Y. Lai3, David J. Tweardy1,6

1Department of Infectious Disease, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

2The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng, China

3Department of Head and Neck Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

4Department of Pharmacology, Baylor College of Medicine, Houston, Texas, USA

5Department of Medicine, Division of Biostatistics, Dan L. Duncan Cancer Center, Section of Hematology/Oncology, Baylor College of Medicine, Houston, Texas, USA

6Department of Molecular & Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Correspondence to:

David J. Tweardy, e-mail: [email protected]

Keywords: STAT3, HNSCC, C188-9, cancer, small molecule

Received: December 14, 2015    Accepted: March 14, 2016    Published: March 25, 2016


While STAT3 has been validated as a target for treatment of many cancers, including head and neck squamous cell carcinoma (HNSCC), a STAT3 inhibitor is yet to enter the clinic. We used the scaffold of C188, a small-molecule STAT3 inhibitor previously identified by us, in a hit-to-lead program to identify C188-9. C188-9 binds to STAT3 with high affinity and represents a substantial improvement over C188 in its ability to inhibit STAT3 binding to its pY-peptide ligand, to inhibit cytokine-stimulated pSTAT3, to reduce constitutive pSTAT3 activity in multiple HNSCC cell lines, and to inhibit anchorage dependent and independent growth of these cells. In addition, treatment of nude mice bearing xenografts of UM-SCC-17B, a radioresistant HNSCC line, with C188-9, but not C188, prevented tumor xenograft growth. C188-9 treatment modulated many STAT3-regulated genes involved in oncogenesis and radioresistance, as well as radioresistance genes regulated by STAT1, due to its potent activity against STAT1, in addition to STAT3. C188-9 was well tolerated in mice, showed good oral bioavailability, and was concentrated in tumors. Thus, C188-9, either alone or in combination with radiotherapy, has potential for use in treating HNSCC tumors that demonstrate increased STAT3 and/or STAT1 activation.

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