Tivantinib (ARQ 197) affects the apoptotic and proliferative machinery downstream of c-MET: role of Mcl-1, Bcl-xl and Cyclin B1
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Shuai Lu1, Helga-Paula Török1, Eike Gallmeier2, Frank T. Kolligs1,3, Antonia Rizzani1, Sabrina Arena4,5, Burkhard Göke1, Alexander L. Gerbes1, Enrico N. De Toni1
1Medizinische Klinik und Poliklinik 2, Klinikum der Universität München, Campus Grosshadern, Munich, Germany
2Department of Gastroenterology, Endocrinology and Metabolism, University Hospital of Marburg, Philipps-University of Marburg, Marburg, Germany
3Department of Internal Medicine and Gastroenterology, HELIOS Klinikum Berlin-Buch, Berlin, Germany
4Department of Oncology, University of Torino, Candiolo, Torino, Italy
5Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy
Enrico De Toni, e-mail: firstname.lastname@example.org
Keywords: HCC, targeted therapies, c-MET, apoptosis
Received: January 28, 2015 Accepted: May 28, 2015 Published: June 10, 2015
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.
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