Human and Mouse VEGFA-Amplified Hepatocellular Carcinomas Are Highly Sensitive to Sorafenib Treatment

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 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);

An Inducible Hepatocellular Carcinoma Model for Preclinical Evaluation of Antiangiogenic Therapy in Adult Mice

“…A study was published in Cancer Discovery since submission of this manuscript demonstrating that VEGF-A amplified HCC are highly sensitive to sorafenib treatment (51). The findings of this study are highly compatible with the findings of our study showing that sorafenib treatment is preferentially acting anti-angiogenic with a very rapid dropout of endothelial cells as early as 24 h after the initiation of treatment (Fig.…”

Animal model studies indicate a candidate biomarker for sorafenib treatment of hepatocellular carcinoma

“…We also measured proliferative indices of treated tumors and found decreased proliferation only in the group harboring the VEGFA amplicon. 3 As predicted by our hypothesis, this was accompanied by downregulation of HGF in amplicon-positive treated tumors. To test whether VEGFA overexpression alone is sufficient to instigate this protumorigenic crosstalk, we transduced a human HCC cell line (Hep3B) with a lentiviral vector overexpressing VEGFA.…”

“…2 Among several amplifications and deletions, 3 we focused on a recurrent amplification in Chr17qB3 harboring the VEGFA gene for 2 main reasons: (1) A syntenic amplification (Chr6p21) was previously reported in several different human tumor types, including HCC; 4 (2) It was previously shown that VEGFA promotes hepatocyte proliferation through induction of hepatocyte growth factor (HGF) in the sinusoidal endothelium. 5 Validating the aCGH results, we found Chr17qB3 amplification in 14% of 93 Mdr2 ¡/¡ HCCs analyzed, close to the frequency of 7-10% reported previously in human HCC.…”

Clinical Drug Response Prediction by Using a Lq Penalized Network-Constrained Logistic Regression Method

“…Moreover, the biomarkers selected by our method include VEGFA (vascular endothelial growth factor A), which plays a key role in angiogenesis. Some research suggests hepatocellular carcinoma (HCC) patients with elevated levels of VEGFA are distinctly sensitive to sorafenib [43], and VEGFA can therefore be used as a biomarker for personalized treatment of HCC with sorafenib [44]. Our result implies that VEGFA may also play a critical role in NSCLC patients with sorafenib.…”