Human and mouse VEGFA-amplified hepatocellular carcinomas are highly sensitive to Sorafenib treatment

Elad Horwitz, Ilan Stein, Mariacarla Andreozzi, Julia Nemeth, Avivit Shoham, Orit Pappo, Nora Schweitzer, Luigi Tornillo, Naama Kanarek, Luca Quagliata, Farid Zreik, Rinnat M. Porat, Rutie Finkelstein, Hendrik Reuter, Ronald Koschny, Tom Ganten, Carolin Mogler, Oren Shibolet, Jochen Hess, Kai BreuhahnMyriam Grunewald, Peter Schirmacher, Arndt Vogel, Luigi Terracciano, Peter Angel, Yinon Ben-Neriah, Eli Pikarsky

Research output: Contribution to journalArticlepeer-review

Abstract

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 amplification, displaying distinct biologic characteristics. Unlike common tumor amplifications, 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, specifically in amplicon-positive mouse HCCs. Sorafenib-the first-line drug in advanced HCC-targets multiple kinases, including VEGFRs, but has only an overall mild beneficial effect. We found that VEGFA amplification specifies 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 -amplified HCCs, suggesting that VEGFA amplification is a potential biomarker for HCC response to VEGF-A-blocking drugs. SIGNIFICANCE: Using a mouse model of inflammation-driven cancer, we identified a subclass of HCC carrying VEGFA amplification, which is particularly sensitive to VEGF-A inhibition. We found that a similar amplification in human HCC identifies patients who favorably responded to sorafenib-the first-line treatment of advanced HCC-which has an overall moderate therapeutic efficacy.

Original languageEnglish
Pages (from-to)730-743
Number of pages14
JournalCancer Discovery
Volume4
Issue number6
DOIs
StatePublished - Jun 2014
Externally publishedYes

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