Hepatocellular Carcinomas Are Highly Sensitive to Sorafenib Treatment

Death rates from hepatocellular carcinoma (HCC) are steadily increasing, yet therapeutic options for advanced HCC are limited. We identify a subset of mouse and human HCCs harboring VEGFA genomic amplifi cation, displaying distinct biologic characteristics. Unlike common tumor amplifi cations, this one seems to work via heterotypic paracrine interactions; stromal VEGF receptors (VEGFR), responding to tumor VEGF-A, produce hepatocyte growth factor (HGF) that reciprocally affects tumor cells. VEGF-A inhibition results in HGF downregulation and reduced proliferation, specifi cally in amplicon-positive mouse HCCs. Sorafenib—the fi rst-line drug in advanced HCC—targets multiple kinases, including VEGFRs, but has only an overall mild benefi cial effect. We found that VEGFA amplifi cation specifi es mouse and human HCCs that are distinctly sensitive to sorafenib. FISH analysis of a retrospective patient cohort showed markedly improved survival of sorafenib-treated patients with VEGFA -amplifi ed HCCs, suggesting that VEGFA amplifi cation is a potential biomarker for HCC response to VEGF-A–blocking drugs. SIGNIFICANCE: Using a mouse model of infl ammation-driven cancer, we identifi ed a subclass of HCC carrying VEGFA amplifi cation, which is particularly sensitive to VEGF-A inhibition. We found that a similar amplifi cation in human HCC identifi es patients who favorably responded to sorafenib—the fi rst-line treatment of advanced HCC—which has an overall moderate therapeutic effi cacy. Cancer Discov; 4(6); 730–43. ©2014 AACR. See related commentary by Luo and Feng, p. 640. Authors’ Affi liations: 1 The Lautenberg Center for Immunology; 2 Department of Developmental Biology and Cancer Research, IMRIC, Hadassah Medical School, Hebrew University; 3 Department of Pathology, HadassahHebrew University Medical Center, Jerusalem; 4 Liver Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; 5 Institute of Pathology, University Hospital Basel, Basel, Switzerland; 6 Division of Signal Transduction and Growth Control (A100), 7 Division of Molecular Genetics (B060), and 8 Junior Group Molecular Mechanisms of Head and Neck Tumors (A102), German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance; 9 Institute of Pathology, University Hospital Heidelberg; Departments of 10 Otolaryngology, Head and Neck Surgery and 11 Internal Medicine, University Hospital Heidelberg, Heidelberg; and 12 Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/). Corresponding Authors: Eli Pikarsky, The Lautenberg Center for Immunology, IMRIC, Hadassah Medical School, Hebrew University, Kiryat Hadassah, P.O.B. 12272, Jerusalem 91120, Israel. Phone: 972-2-675-8202; Fax: 972-2-642-6268; E-mail: [email protected] ; and Yinon Ben-Neriah, The Lautenberg Center for Immunology, IMRIC, Hadassah Medical School, Hebrew University, Kiryat Hadassah, P.O.B. 12272, Jerusalem 91120, Israel. Phone: 972-2-675-8718; E-mail: [email protected] doi: 10.1158/2159-8290.CD-13-0782 ©2014 American Association for Cancer Research. on June 15, 2017. © 2014 American Association for Cancer Research. cancerdiscovery.aacrjournals.org Downloaded from Published OnlineFirst March 31, 2014; DOI: 10.1158/2159-8290.CD-13-0782