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 BET inhibitors.,PLX51107 was ineffective in vivo, but the combination of a FGFR inhibitor, AZD4547, and PLX51107 significantly suppressed the growth of xenograft UM tumors formed from subcutaneous inoculation of UM cells with HSCs and orthotopically in the liver.,These results suggest that co‐targeting of FGFR signaling is required to increase the responses of metastatic UM to BET inhibitors.
Hepatocyte growth factor (HGF)/ mesenchymal-epithelial transition factor (c-MET) signaling is involved in complex cellular programs that are important for embryonic development and tissue regeneration, but its activity is also utilized by cancer cells during tumor progression.,HGF and c-MET usually mediate heterotypic cell-cell interactions, such as epithelial-mesenchymal, including tumor-stroma interactions.,In the skin, dermal fibroblasts are the main source of HGF.,The presence of c-MET on keratinocytes is crucial for wound healing in the skin.,HGF is not released by normal melanocytes, but as melanocytes express c-MET, they are receptive to HGF, which protects them from apoptosis and stimulates their proliferation and motility.,Dissimilar to melanocytes, melanoma cells not only express c-MET, but also release HGF, thus activating c-MET in an autocrine manner.,Stimulation of the HGF/c-MET pathways contributes to several processes that are crucial for melanoma development, such as proliferation, survival, motility, and invasiveness, including distant metastatic niche formation.,HGF might be a factor in the innate and acquired resistance of melanoma to oncoprotein-targeted drugs.,It is not entirely clear whether elevated serum HGF level is associated with low progression-free survival and overall survival after treatment with targeted therapies.,This review focuses on the role of HGF/c-MET signaling in melanoma with some introductory information on its function in skin and melanocytes.