Tivantinib (ARQ 197) affects the apoptotic and proliferative machinery downstream of c-MET: Role of Mcl-1, Bcl-xl and Cyclin B1

Shuai Lu, Helga Paula Török, Eike Gallmeier, Frank T. Kolligs, Antonia Rizzani, Sabrina Arena, Burkhard Göke, Alexander L. Gerbes, Enrico N. De Toni

Research output: Contribution to journalArticle

Abstract

Tivantinib, a c-MET inhibitor, is investigated as a second-line treatment of HCC. It was shown that c-MET overexpression predicts its efficacy. Therefore, a phase-3 trial of tivantinib has been initiated to recruit "c-MET-high"patients only. However, recent evidence indicates that the anticancer activity of tivantinib is not due to c-MET inhibition, suggesting that c-MET is a predictor of response to this compound rather than its actual target. By assessing the mechanisms underlying the anticancer properties of tivantinib we showed that this agent causes apoptosis and cell cycle arrest by inhibiting the anti-apoptotic molecules Mcl-1 and Bcl-xl, and by increasing Cyclin B1 expression regardless of c-MET status. However, we found that tivantinib might antagonize the antiapoptotic effects of c-MET activation since HGF enhanced the expression of Mcl-1 and Bcl-xl. In summary, we show that the activity of tivantinib is independent of c-MET and describe Mcl-1, Bcl-xl and Cyclin B1 as effectors of its antineoplastic effects in HCC cells. We suggest that the predictive effect of c-MET expression in part reflects the c-MET-driven overexpression of Mcl-1 and Bcl-xl in c-MET-high patients and that these molecules are considered as possible response predictors.

Original languageEnglish
Pages (from-to)22167-22178
Number of pages12
JournalOncotarget
Volume6
Issue number26
Publication statusPublished - 2015

Keywords

  • Apoptosis
  • C-MET
  • HCC
  • Targeted therapies

ASJC Scopus subject areas

  • Oncology

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    Lu, S., Török, H. P., Gallmeier, E., Kolligs, F. T., Rizzani, A., Arena, S., Göke, B., Gerbes, A. L., & De Toni, E. N. (2015). Tivantinib (ARQ 197) affects the apoptotic and proliferative machinery downstream of c-MET: Role of Mcl-1, Bcl-xl and Cyclin B1. Oncotarget, 6(26), 22167-22178.