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

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.

Chua V ，Orloff M ，Teh JL ，Sugase T ，Liao C ，Purwin TJ ，Lam BQ ，Terai M ，Ambrosini G ，Carvajal RD ，Schwartz G ，Sato T ，Aplin AE ... -  《-》

Role of Fibroblast Growth Factors in the Crosstalk of Hepatic Stellate Cells and Uveal Melanoma Cells in the Liver Metastatic Niche.

Seitz T ，John N ，Sommer J ，Dietrich P ，Thasler WE ，Hartmann A ，Evert K ，Lang SA ，Bosserhoff A ，Hellerbrand C ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

Inhibition of NF-κB-Dependent Signaling Enhances Sensitivity and Overcomes Resistance to BET Inhibition in Uveal Melanoma.

Bromodomain and extraterminal protein inhibitors (BETi) are epigenetic therapies aimed to target dysregulated gene expression in cancer cells. Despite early successes of BETi in a range of malignancies, the development of drug resistance may limit their clinical application. Here, we evaluated the mechanisms of BETi resistance in uveal melanoma, a disease with little treatment options, using two approaches: a high-throughput combinatorial drug screen with the clinical BET inhibitor PLX51107 and RNA sequencing of BETi-resistant cells. NF-κB inhibitors synergistically sensitized uveal melanoma cells to PLX51107 treatment. Furthermore, genes involved in NF-κB signaling were upregulated in BETi-resistant cells, and the transcription factor CEBPD contributed to the mechanism of resistance. These findings suggest that inhibitors of NF-κB signaling may improve the efficacy of BET inhibition in patients with advanced uveal melanoma. SIGNIFICANCE: These findings provide evidence that inhibitors of NF-κB signaling synergize with BET inhibition in in vitro and in vivo models, suggesting a clinical utility of these targeted therapies in patients with uveal melanoma.

Ambrosini G ，Do C ，Tycko B ，Realubit RB ，Karan C ，Musi E ，Carvajal RD ，Chua V ，Aplin AE ，Schwartz GK ... -  《-》

Activation of the FGF2/FGFR1 autocrine loop for cell proliferation and survival in uveal melanoma cells.

Lefèvre G ，Babchia N ，Calipel A ，Mouriaux F ，Faussat AM ，Mrzyk S ，Mascarelli F ... -  《-》

Targeting primary and metastatic uveal melanoma with a G protein inhibitor.

Uveal melanoma (UM) is the most common intraocular tumor in adults. Nearly half of UM patients develop metastatic disease and often succumb within months because effective therapy is lacking. A novel therapeutic approach has been suggested by the discovery that UM cell lines driven by mutant constitutively active Gq or G11 can be targeted by FR900359 (FR) or YM-254890, which are bioavailable, selective inhibitors of the Gq/11/14 subfamily of heterotrimeric G proteins. Here, we have addressed the therapeutic potential of FR for UM. We found that FR inhibited all oncogenic Gq/11 mutants reported in UM. FR arrested growth of all Gq/11-driven UM cell lines tested, but induced apoptosis only in a few. Similarly, FR inhibited growth of, but did not efficiently kill, UM tumor cells from biopsies of primary or metastatic tumors. FR evoked melanocytic redifferentiation of UM tumor cells with low (class 1), but not high (class 2), metastatic potential. FR administered systemically below its LD50 strongly inhibited growth of PDX-derived class 1 and class 2 UM tumors in mouse xenograft models and reduced blood pressure transiently. FR did not regress xenografted UM tumors or significantly affect heart rate, liver function, hematopoiesis, or behavior. These results indicated the existence of a therapeutic window in which FR can be explored for treating UM and potentially other diseases caused by constitutively active Gq/11.

Onken MD ，Makepeace CM ，Kaltenbronn KM ，Choi J ，Hernandez-Aya L ，Weilbaecher KN ，Piggott KD ，Rao PK ，Yuede CM ，Dixon AJ ，Osei-Owusu P ，Cooper JA ，Blumer KJ ... -  《-》