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Supplementary Tables from Human and Mouse VEGFA-Amplified Hepatocellular Carcinomas Are Highly Sensitive to Sorafenib Treatment
journal contribution
posted on 2023-04-03, 20:49 authored by 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 Breuhahn, Myriam Grunewald, Peter Schirmacher, Arndt Vogel, Luigi Terracciano, Peter Angel, Yinon Ben-Neriah, Eli PikarskyPDF file 145K, Tables containing information about genes residing on the amplicon and compiled data
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ARTICLE 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. Cancer Discov; 4(6); 730–43. ©2014 AACR.See related commentary by Luo and Feng, p. 640This article is highlighted in the In This Issue feature, p. 621Usage metrics
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AngiogenesisAngiogenic factors and receptorsBiomarkersCancer InterceptionBiomarkers and interventionCancer PreventionEarly DetectionIdentification of new risk factorsDna Damage And RepairGene amplificationDrug MechanismsCellular responses to anticancer drugsGastrointestinal CancersLiver cancerGene TechnologiesComparative genomicsPreclinical ModelsAnimal models of cancerTumor MicroenvironmentTumor-stromal cell interactions
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