Abstract 1026: Oncogenic alterations in FGFR3 and ERBB2 lead to ligand-independent activation of PPARG in bladder cancer

Abstract

Abstract PPARG is genomically activated in muscle-invasive bladder cancer through focal PPARG gene amplification and hotspot mutations in its heterodimer partner, RXRA. However, more than half of the PPARG-activated bladder tumors and cell lines do not have identifiable somatic alterations in either PPARG or RXRA. Using a PPARG-driven reporter assay in RT112 bladder cancer cell line, we screened probe compounds to identify candidate drivers of ligand-independent PPARG activation. We found that pan-FGFR inhibitors and MEK1/2 inhibitors antagonized the PPARG-driven reporter assay with potency similar to reported values for their cognate targets (1-20 nM) and interestingly, RT112 cells carry an FGFR3-TACC3 oncogenic fusion. In addition to the expected effects of these inhibitors on phospho-MEK1/2 and phospho-ERK1/2, they also inhibited production of canonical PPARG targets, including FABP4. In a second subset of cell lines, a parallel story was also observed for the effects of ERBB2 inhibitors in ERBB2 hotspot mutant bladder cancer. Taken together, these data uncover additional mechanisms for functional activation of PPARG in bladder cancer, suggest potential resistance mechanisms for FGFR and ERBB2 inhibitors, and provide a rationale for therapeutic combinations of PPARG modulators. Citation Format: Jonathan T. Goldstein, Ashton C. Berger, Craig A. Strathdee, Matthew Meyerson. Oncogenic alterations in FGFR3 and ERBB2 lead to ligand-independent activation of PPARG in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1026.