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 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.
Highlights
Alterations in transcriptional programs promote tumor development and progression and are targetable by bromodomain and extraterminal (BET) protein inhibitors
A pre-treatment biopsy was collected from the liver metastases prior to the first cycle of PLX51107 treatment, and a post-treatment biopsy was obtained from the growing mass in the peritoneum shortly after removal of the patient from the protocol (Fig 1A)
We found that fibroblast growth factor 2 (FGF2), but not other growth factors, significantly provided resistance to growth suppression by BET inhibitors in metastatic uveal melanoma (UM) cell lines
Summary
Alterations in transcriptional programs promote tumor development and progression and are targetable by bromodomain and extraterminal (BET) protein inhibitors. BET inhibitors increased FGFR protein expression in UM cell lines and in patient tumor samples. 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
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