Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by Oncogenomic screening

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Hepatocellular carcinoma (HCC) frequently exhibits gene amplification at the 11q13.3 locus.
• CCND1 is commonly considered the primary oncogene in this amplicon.
• The role of other amplified genes, such as FGF19, requires further elucidation.

Purpose of the Study:

• To investigate the oncogenic roles of amplified genes in hepatocellular carcinoma (HCC).
• To determine the specific contribution of FGF19 to HCC development and progression.
• To evaluate the therapeutic potential of targeting FGF19 in HCC.

Main Methods:

• Screening of 124 amplified genes in a mouse hepatoblast model.
• Forward-transformation assays in human HCC cells.
• RNA interference (RNAi)-mediated gene inhibition.
• Inhibition studies using an anti-FGF19 antibody.

Main Results:

• Identified 18 tumor-promoting genes, including CCND1 and FGF19.
• FGF19 was confirmed as an equally important driver gene in HCC as CCND1.
• RNAi knockdown of CCND1 or FGF19, and anti-FGF19 antibody treatment, inhibited HCC cell growth and tumorigenicity.
• 11q13.3 amplification was associated with sensitivity to anti-FGF19 therapy.

Conclusions:

• FGF19 is a critical oncogenic driver in HCC, comparable to CCND1.
• Targeting FGF19 offers a potential therapeutic strategy for HCC.
• 11q13.3 amplicon status can serve as a predictive biomarker for anti-FGF19 therapy response.