pathway mapping identifies wild-type as a targetable metabolic node in gastric cancer.

OBJECTIVE

Gastric cancer (GC) is a leading cause of cancer mortality. Previous studies have shown that is specifically overexpressed in GC and functionally required for GC development. In this study, we investigated, on a genome-wide scale, target genes of HNF4α and oncogenic pathways driven by HNF4α and HNF4α target genes.

DESIGN

We performed HNF4α chromatin immunoprecipitation followed by sequencing across multiple GC cell lines, integrating HNF4α occupancy data with (epi)genomic and transcriptome data of primary GCs to define HNF4α target genes of and relevance. To investigate mechanistic roles of and HNF4α targets, we performed cancer metabolic measurements, drug treatments and functional assays including murine xenograft experiments.

RESULTS

Gene expression analysis across 19 tumour types revealed to be specifically upregulated in GCs. Unbiased pathway analysis revealed organic acid metabolism as the top -regulated pathway, orthogonally supported by metabolomic analysis. Isocitrate dehydrogenase 1 () emerged as a convergent direct target gene regulating GC metabolism. We show that wild-type is essential for GC cell survival, and that certain GC cells can be targeted by IDH1 inhibitors.

CONCLUSIONS

Our results highlight a role for in sustaining GC oncogenic metabolism, through the regulation of . Drugs targeting wild-type may thus have clinical utility in GCs exhibiting overexpression, expanding the role of in cancer beyond mutated malignancies.