Stromal fibroblast growth factor 2 reduces the efficacy of bromodomain inhibitors in uveal melanoma.

ABSTRACT: Alterations in transcriptional programs promote tumor development and progression and are targetable by bromodomain and extraterminal (BET) protein inhibitors. However, in a multi-site clinical trial testing the novel BET inhibitor, PLX51107, in solid cancer patients, liver metastases of uveal melanoma (UM) patients progressed rapidly following treatment. Mechanisms of resistance to BET inhibitors in UM are unknown. We show that fibroblast growth factor 2 (FGF2) rescued UM cells from growth inhibition by BET inhibitors, and FGF2 effects were reversible by FGF receptor (FGFR) inhibitors. BET inhibitors also increased FGFR protein expression in UM cell lines and in patient tumor samples. Hepatic stellate cells (HSCs) secrete FGF2, and HSC-conditioned medium provided resistance of UM cells to

SUBMITTER: Chua V 

PROVIDER: S-EPMC6365926 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature