Research Papers:

Regorafenib (Stivarga) pharmacologically targets epithelial-mesenchymal transition in colorectal cancer

Li-Ching Fan, Hao-Wei Teng, Chung-Wai Shiau, Wei-Tien Tai, Man-Hsin Hung, Shung-Haur Yang, Jeng-Kai Jiang and Kuen-Feng Chen _

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Oncotarget. 2016; 7:64136-64147. https://doi.org/10.18632/oncotarget.11636

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Li-Ching Fan1,2, Hao-Wei Teng3,7, Chung-Wai Shiau4, Wei-Tien Tai1,2, Man-Hsin Hung5,7, Shung-Haur Yang6,7, Jeng-Kai Jiang6,7, Kuen-Feng Chen1,2

1Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan

2National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan

3Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

4Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan

5Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan

6Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan

7School of Medicine, National Yang-Ming University, Taipei, Taiwan

Correspondence to:

Kuen-Feng Chen, email: [email protected]

Keywords: regorafenib, EMT, SHP-1, STAT3, CRC

Received: March 11, 2016     Accepted: August 13, 2016     Published: August 26, 2016


Epithelial-to-mesenchymal transition (EMT) is well-known to evoke cancer invasion/metastasis, leading to a high frequency of mortality in patients with metastatic colorectal cancer (mCRC). Protein tyrosine phosphatase (PTPase)-targeted therapy has been identified as a novel cancer therapeutic. Previously, we proved that sorafenib with anti-EMT potency prevents TGF-β1-induced EMT/invasion by directly activating SH2-domain-containing phosphatase 1 (SHP-1)-dependent p-STAT3Tyr705 suppression in hepatocellular carcinoma. Regorafenib has a closely related chemical structure as sorafenib and is approved for the pharmacotherapy of mCRC. Herein, we evaluate whether regorafenib activates PTPase SHP-1 in the same way as sorafenib to abolish EMT-related invasion/metastasis in CRC. Notably, regorafenib exerted potent anti-EMT activity to curb TGF-β1-induced EMT/invasion in vitro as well inhibited lung metastatic outgrowth of SW480 mesenchymal cells in vivo. Mechanistically, regorafenib-enhanced SHP-1 activity significantly impeded TGF-β1-induced EMT/invasion via low p-STAT3Tyr705 level as proved by a SHP-1 inhibitor or siRNA-mediated SHP-1 depletion. Conversely, overexpression of SHP-1 further enhanced the inhibitory effects of regorafenib on TGF-β1-induced p-STAT3Tyr705 and EMT/invasion. Regorafenib directly activates SHP-1 by potently relieving the autoinhibited N-SH2 domain of SHP-1 to inhibit TGF-β1-induced p-STAT3Tyr705 and EMT/invasion. Importantly, the clinical evidence indicated that SHP-1 was positively correlated with E-cadherin and that significantly determined the overall survival of CRC patients. This result further confirms our in vitro data that SHP-1 is a negative regulatory PTPase in EMT regulation and serves as a pharmacological target for mCRC therapy. Collectively, activating PTPase SHP-1 by regorafenib focusing on its anti-EMT activity might be a useful pharmacotherapy for mCRC.

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