ABT-869, a multi-targeted tyrosine kinase inhibitor, in combination with rapamycin is effective for subcutaneous hepatocellular carcinoma xenograft

Viraj J. Jasinghe, Zhigang Xie, Jianbiao Zhou, Jiaying Khng, Lai Fong Poon, Palaniyandi Senthilnathan, Keith B. Glaser, Daniel H. Albert, Steven K. Davidsen, Chien Shing Chen

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Background/Aims: Receptor tyrosine kinase inhibitors (RTKIs) and mTOR inhibitors are potential novel anticancer therapies for HCC. We hypothesized that combination targeted on distinctive signal pathways would provide synergistic therapeutics. Methods: ABT-869, a novel RTKI, and rapamycin were investigated in HCC pre-clinical models. Results: Rapamycin, but not ABT-869, inhibited in vitro growth of Huh7 and SK-HEP-1 HCC cells in a dose dependant manner. However, in subcutaneous Huh7 and SK-HEP-1 xenograft models, either ABT-869 or rapamycin can significantly reduce tumor burden. Combination treatment reduced the tumors to the lowest volume (95 ± 20 mm3), and was significantly better than single agent treatment (p < 0.05). Immunohistochemical staining of tumor shows that ABT-869 potently inhibits VEGF in HCC in vivo. In addition, the MAPK signaling pathway has been inhibited by significant inhibition of phosphorylation of p44/42 MAP kinase by ABT-869 in vivo. Rapamycin inhibits phosphorylation of p70 S6 kinase and 4E-BP-1, downstream targets of mTOR, and decreases VEGF. Combination treatment showed synergistic effect on expression levels of p27 in vivo. Dramatic inhibition of neo-angiogenesis by ABT-869 was also demonstrated. Conclusions: HCC could potentially be treated with the combination treatment of ABT-869 and rapamycin. Clinical trials on combination therapy are warranted.

Original languageEnglish
Pages (from-to)985-997
Number of pages13
JournalJournal of Hepatology
Volume49
Issue number6
DOIs
StatePublished - Dec 2008

Bibliographical note

Funding Information:
This work is supported by Singapore Cancer Syndicate Grant –TN0031, AN0038, and Terry Fox Run Cancer Research Grant 2004 (C.-S. Chen).

Keywords

  • ABT-869
  • Angiogenesis
  • Hepatocellular carcinoma
  • Rapamycin
  • Tyrosine kinase inhibitor
  • mTOR pathway

ASJC Scopus subject areas

  • Hepatology

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