TY - JOUR
T1 - Allosteric MEK1/2 inhibitor Refametinib (BAY 86-9766) in combination with sorafenib exhibits antitumor activity in preclinical murine and rat models of hepatocellular carcinoma
AU - Schmieder, Roberta
AU - Puehler, Florian
AU - Neuhaus, Roland
AU - Kissel, Maria
AU - Adjei, Alex A.
AU - Miner, Jeffrey N.
AU - Mumberg, Dominik
AU - Ziegelbauer, Karl
AU - Scholz, Arne
N1 - Funding Information:
Abbreviations: HCC, hepatocellular carcinoma; HBV, hepatitis B virus; HCV, hepatitis C virus; VEGFRs, vascular endothelial growth factor receptors; OS, overall survival; AFP, alpha-fetoprotein Address all correspondence to: Florian Puehler, PhD, Bayer Pharma AG, Muellerstr. 178, 13353 Berlin, Germany. E-mail: florian.puehler@bayer.com 1This work was supported by Bayer HealthCare (Berlin, Germany) and Ardea Biosciences (San Diego, CA). Writing assistance was provided by Synapse Medical Communications (New York, NY). R.S., F.P., R.N., M.K., D.M., K.Z., and A.S. are stockholders and/or employees of Bayer Pharma AG. Prior presentations: Part of this work was presented at the American Association for Cancer Research–National Cancer Institute–European Organisation for Research and Treatment of Cancer meeting in San Francisco on November 12 to 16, 2011. 2This article refers to supplementary materials, which are designated by Figures W1 to W3 and are available online at www.neoplasia.com. 3These authors contributed equally to this work. Received 22 April 2013; Revised 9 September 2013; Accepted 9 September 2013 Copyright © 2013 Neoplasia Press, Inc. All rights reserved 1522-8002/13/$25.00 DOI 10.1593/neo.13812
PY - 2013/10
Y1 - 2013/10
N2 - OBJECTIVE: The objectives of the study were to evaluate the allosteric mitogen-activated protein kinase kinase (MEK) inhibitor BAY 86-9766 in monotherapy and in combination with sorafenib in orthotopic and subcutaneous hepatocellular carcinoma (HCC) models with different underlying etiologies in two species. DESIGN: Antiproliferative potential of BAY 86-9766 and synergistic effects with sorafenib were studied in several HCC cell lines. Relevant pathway signaling was studied in MH3924a cells. For in vivo testing, the HCC cells were implanted subcutaneously or orthotopically. Survival and mode of action (MoA) were analyzed. RESULTS: BAY 86-9766 exhibited potent antiproliferative activity in HCC cell lines with half-maximal inhibitory concentration values ranging from 33 to 762 nM. BAY 86-9766 was strongly synergistic with sorafenib in suppressing tumor cell proliferation and inhibiting phosphorylation of the extracellular signal-regulated kinase (ERK). BAY 86-9766 prolonged survival in Hep3B xenografts, murine Hepa129 allografts, and MH3924A rat allografts. Additionally, tumor growth, ascites formation, and serum alpha-fetoprotein levels were reduced. Synergistic effects in combination with sorafenib were shown in Huh-7, Hep3B xenografts, and MH3924A allografts. On the signaling pathway level, the combination of BAY 86-9766 and sorafenib led to inhibition of the upregulatory feedback loop toward MEK phosphorylation observed after BAY 86-9766 monotreatment. With regard to the underlying MoA, inhibition of ERK phosphorylation, tumor cell proliferation, and microvessel density was observed in vivo. CONCLUSION: BAY 86-9766 shows potent single-agent antitumor activity and acts synergistically in combination with sorafenib in preclinical HCC models. These results support the ongoing clinical development of BAY 86-9766 and sorafenib in advanced HCC.
AB - OBJECTIVE: The objectives of the study were to evaluate the allosteric mitogen-activated protein kinase kinase (MEK) inhibitor BAY 86-9766 in monotherapy and in combination with sorafenib in orthotopic and subcutaneous hepatocellular carcinoma (HCC) models with different underlying etiologies in two species. DESIGN: Antiproliferative potential of BAY 86-9766 and synergistic effects with sorafenib were studied in several HCC cell lines. Relevant pathway signaling was studied in MH3924a cells. For in vivo testing, the HCC cells were implanted subcutaneously or orthotopically. Survival and mode of action (MoA) were analyzed. RESULTS: BAY 86-9766 exhibited potent antiproliferative activity in HCC cell lines with half-maximal inhibitory concentration values ranging from 33 to 762 nM. BAY 86-9766 was strongly synergistic with sorafenib in suppressing tumor cell proliferation and inhibiting phosphorylation of the extracellular signal-regulated kinase (ERK). BAY 86-9766 prolonged survival in Hep3B xenografts, murine Hepa129 allografts, and MH3924A rat allografts. Additionally, tumor growth, ascites formation, and serum alpha-fetoprotein levels were reduced. Synergistic effects in combination with sorafenib were shown in Huh-7, Hep3B xenografts, and MH3924A allografts. On the signaling pathway level, the combination of BAY 86-9766 and sorafenib led to inhibition of the upregulatory feedback loop toward MEK phosphorylation observed after BAY 86-9766 monotreatment. With regard to the underlying MoA, inhibition of ERK phosphorylation, tumor cell proliferation, and microvessel density was observed in vivo. CONCLUSION: BAY 86-9766 shows potent single-agent antitumor activity and acts synergistically in combination with sorafenib in preclinical HCC models. These results support the ongoing clinical development of BAY 86-9766 and sorafenib in advanced HCC.
UR - http://www.scopus.com/inward/record.url?scp=84887093344&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84887093344&partnerID=8YFLogxK
U2 - 10.1593/neo.13812
DO - 10.1593/neo.13812
M3 - Article
C2 - 24204195
AN - SCOPUS:84887093344
SN - 1522-8002
VL - 15
SP - 1161
EP - 1171
JO - Neoplasia (United States)
JF - Neoplasia (United States)
IS - 10
ER -