Nintedanib (BIBF-1120) inhibits hepatocellular carcinoma growth independent of angiokinase activity

• Published in: Journal of hepatology 2014-07, Vol.61 (1), p.89-97
• Main Authors: Tai, Wei-Tien, Shiau, Chung-Wai, Li, Yong-Shi, Chang, Chun-Wei, Huang, Jui-Wen, Hsueh, Ting-Ting, Yu, Hui-Chuan, Chen, Kuen-Feng
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Binding Sites; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - enzymology; Carcinoma, Hepatocellular - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Gastroenterology and Hepatology; HCC; Humans; Indoles - therapeutic use; Liver Neoplasms - drug therapy; Liver Neoplasms - enzymology; Liver Neoplasms - pathology; Male; Mice; Mice, Nude; Models, Molecular; Mutant Proteins - chemistry; Mutant Proteins - genetics; Mutant Proteins - metabolism; Nintedanib; Protein Conformation; Protein Kinase Inhibitors - therapeutic use; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - chemistry; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - metabolism; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - chemistry; SHP-1; Signal Transduction - drug effects; STAT3; STAT3 Transcription Factor - metabolism; VEGFR2; Xenograft Model Antitumor Assays
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2014.03.017

Background & Aims Nintedanib, a triple angiokinase inhibitor, is currently being evaluated against advanced HCC in phase I/II clinical trials. Here, we report the underlying molecular mechanism by which nintedanib (BIBF-1120) induces an anti-HCC effect. Methods To further elucidate whether the effect of nintedanib on SHP-1 is dependent on its angiokinase inhibition activity, we developed a novel kinase-independent derivative of nintedanib, ΔN. HCC cell lines were treated with nintedanib or its derivative (ΔN) and apoptosis, signal transduction, and phosphatase activity were analyzed. Purified SHP-1 proteins or HCC cells expressing deletion N-SH2 domain or D61A point mutants were used to investigate the potential effect of nintedanib on SHP-1. In vivo efficacy was determined in nude mice with HCC subcutaneous xenografts (n ⩾ 8 mice). Results Nintedanib induced anti-proliferation in HCC cell lines by targeting STAT3. Ectopic STAT3 abolished nintedanib-mediated apoptosis in HCC cells. Nintedanib further activated SHP-1 in purified SHP-1 proteins suggesting that nintedanib directly affects SHP-1 for STAT3 inhibition. HCC cells or recombinant SHP-1 proteins expressing deletion of N-SH2 domain or D61A mutants restored the activity of nintedanib suggesting that the auto-inhibition structure of SHP-1 was relieved by nintedanib. Although ΔN only retained the backbone of nintedanib without kinase activity, ΔN still induced substantial anti-HCC activity in vitro and in vivo by targeting STAT3. Conclusions Nintedanib induced significant anti-HCC activity independent of angiokinase inhibition activity in a preclinical HCC model by relieving autoinhibition of SHP-1. Our findings provide new mechanistic insight into the inhibition of HCC growth by nintedanib.