Purine biosynthesis and related enzymes play the oncogenic function in FGFR3 mutant urothelial carcinoma

Abstract

Urothelial carcinoma (UC), as one of the malignant tumors, has a high incidence, mortality, and poor survival rate. FGFR3 is one of the frequency mutation genetic events of UC. Recent studies have reported that FGFR3 mutations are associated with lower aggressiveness and better prognosis of UC, and small molecule compounds with FGFR3 mutations have been developed and treated. However, they are still limited, especially for wild‐type cells. We used Ingenuity Pathways Analysis (IPA) to analyze the significantly expression of 351 genes (>2‐fold change cutoff value) between FGFR3 wild‐type and mutation/fusion UC cells by FGFR3 inhibitors treatment. Through the predicted canonical pathways, several metabolism‐related events have been regulated, including purine biosynthesis. Focusing on de novo purine biosynthesis, we found that several involved enzymes are upregulated in UC. In addition, we have also observed that several enzymes are inhibited by FGFR3 inhibitors in mutant cells, but not in wild type. We then hypothesized that purine biosynthetic events might confer drug resistance and promote UC tumorigenicity. To verify our observations, we determined the expression level of purine biosynthesis after FGFR3 classification. The results indicate a similar trend in clinical cohorts that overexpression of purine biosynthesis genes in FGFR3 wild‐type. Moreover, combining these genes can be used as an independent prognostic factor (HR=1.41, p=0.026). We further established the overexpression of purine biosynthesis genes in some FGFR3 mutant UC cells. We determined that purine biosynthesis genes cause FGFR3 mutations models to be more prone to mesenchymal and metastatic than controls. Our studies also observed that FGFR3 wild‐type cells promote UC cell radioresistance via purine biosynthesis and further activate the homologous recombination repair mechanism. Combining all evidence, we claim that purine biosynthesis should be focused and regarded as a novel strategy against UC.