FGF/FGFR inhibitors downmodulates c-Myc oncoprotein and hampers the growth of adrenocortical carcinoma

: Adrenocortical carcinoma (ACC) is a rare endocrine neoplastic disease that originates from the cortical cortex of adrenal gland. Unfortunately, after complete resection of the tumor, ACC relapses either locally or with distant metastasis in about 74 % of patients and for these patients the therapeutic options are still severely limited. In this study we demonstrate that the system composed by the fibroblast growth factors (FGFs) and their receptors (FGFRs) might represent a promising therapeutic target for ACC. Indeed, human ACC specimens and cell lines express FGF ligands and FGF receptors and show FGFR activation, suggesting the presence of an autocrine FGF/FGFR loop of stimulation able to sustain ACC growth. Accordingly, inhibition of FGFR activation by TK inhibitors (erdafitinib and infigratinib) or FGF trapping (by NSC12) significantly hampered ACC growth and survival in vitro. Importantly, oral administration of erdafitinib strongly affected tumor growth in vivo by reducing tumor cell proliferation/survival and tumor angiogenesis. Mechanistically, FGF/FGFR inhibition in ACC cells strongly decreased the levels of the oncoprotein c-Myc and induced oxidative stress and DNA damage, leading to reduced tumor cell proliferation and increased tumor cell apoptosis. Altogether these results demonstrate for the first time the impact of FGF/FGFR blockade on ACC cell growth and survival both in vitro and in vivo. This study may set the rationale to start clinical trials investigating the therapeutic potential of FDA approved FGFR-TK inhibitors for the treatment of aggressive ACC.