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 ... -  《-》

The pharmacological NF-κB inhibitor BAY11-7082 induces cell apoptosis and inhibits the migration of human uveal melanoma cells.

Hu S ，Luo Q ，Cun B ，Hu D ，Ge S ，Fan X ，Chen F ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

Co-inhibition of BET proteins and NF-κB as a potential therapy for colorectal cancer through synergistic inhibiting MYC and FOXM1 expressions.

Wu T ，Wang G ，Chen W ，Zhu Z ，Liu Y ，Huang Z ，Huang Y ，Du P ，Yang Y ，Liu CY ，Cui L ... -  《Cell Death & Disease》

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 ... -  《-》

HDAC Inhibition Enhances the In Vivo Efficacy of MEK Inhibitor Therapy in Uveal Melanoma.

The clinical use of MEK inhibitors in uveal melanoma is limited by the rapid acquisition of resistance. This study has used multiomics approaches and drug screens to identify the pan-HDAC inhibitor panobinostat as an effective strategy to limit MEK inhibitor resistance.Experimental Design: Mass spectrometry-based proteomics and RNA-Seq were used to identify the signaling pathways involved in the escape of uveal melanoma cells from MEK inhibitor therapy. Mechanistic studies were performed to evaluate the escape pathways identified, and the efficacy of the MEK-HDAC inhibitor combination was demonstrated in multiple in vivo models of uveal melanoma. We identified a number of putative escape pathways that were upregulated following MEK inhibition, including the PI3K/AKT pathway, ROR1/2, and IGF-1R signaling. MEK inhibition was also associated with increased GPCR expression, particularly the endothelin B receptor, and this contributed to therapeutic escape through ET-3-mediated YAP signaling. A screen of 289 clinical grade compounds identified HDAC inhibitors as potential candidates that suppressed the adaptive YAP and AKT signaling that followed MEK inhibition. In vivo, the MEK-HDAC inhibitor combination outperformed either agent alone, leading to a long-term decrease of tumor growth in both subcutaneous and liver metastasis models and the suppression of adaptive PI3K/AKT and YAP signaling. Together, our studies have identified GPCR-mediated YAP activation and RTK-driven AKT signaling as key pathways involved in the escape of uveal melanoma cells from MEK inhibition. We further demonstrate that HDAC inhibition is a promising combination partner for MEK inhibitors in advanced uveal melanoma.

Faião-Flores F ，Emmons MF ，Durante MA ，Kinose F ，Saha B ，Fang B ，Koomen JM ，Chellappan SP ，Maria-Engler SS ，Rix U ，Licht JD ，Harbour JW ，Smalley KSM ... -  《-》