Abstract 1746: FGFR3 inhibition is a highly effective therapy in MTAP-deficient, FGFR3 altered urothelial carcinoma

Abstract FGFR3 alterations are observed in more than 15% of metastatic urothelial cancers. In 2019, erdafitinib was the first FGFR inhibitor approved by the FDA for treatment of FGFR3-altered metastatic urothelial cancer with an objective response rate of 40%. However, a high percentage of patients with FGFR3 alterations still do not respond to erdafitinib. Thus, it is critical to identify additional biomarkers to stratify patients and increase the therapeutic efficacy of FGFR inhibitors. Our previous study identified that FGFR3 was more frequently altered in methylthioadenosine phosphorylase (MTAP)-deficient tumors (MTAP-deficient: 31% vs MTAP-proficient: 8%), which raises our interest to investigate whether MTAP deficiency leads to enhanced dependency on FGFR3 activity and increases tumor treatment response to FGFR inhibitors. Here, we report that IC50 of FGFR inhibitors is significantly lower in MTAP-deficient tumors compared to MTAP-proficient tumors. Notably, an MTAP enzyme, which was developed to deplete its substrate, MTA [a known inhibitor of protein arginine methyltransferase 5 (PRMT5)], significantly increases the PRMT5 activity and results in resistance to FGFR inhibitors in MTAP-deficient tumors. Moreover, our data demonstrate that PRMT5 inhibition sensitizes MTAP-proficient tumors to FGFR inhibitors, suggesting that inhibition of PRMT5 activity by MTA contributes to tumor response to FGFR inhibitors in MTAP-deficient tumors. Taken together, our current findings suggest that: 1) MTAP deficiency could serve as a rational biomarker to predict response of FGFR inhibitors and; 2) FGFR inhibitors may be highly effective therapies for patients with MTAP-deficient, FGFR3 altered urothelial cancer. Citation Format: Yu-Yi Chu, Jianfeng Chen, Cindy Y. Jiang, Ying Mei, Yuxue Zhang, Arlene Siefker-Radtke, Jianjun Gao. FGFR3 inhibition is a highly effective therapy in MTAP-deficient, FGFR3 altered urothelial carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1746.