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

Abstract

Purpose: 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. Results: 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. Conclusions: Together, our studies have identified GPCRmediated 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.

Decitabine limits escape from MEK inhibition in uveal melanoma

“…The uveal melanoma cell lines 92.1, Mel270, MP41, Mel202, and Mel290 were used as previously described (Faiao‐Flores et al, ). The identities of the cell lines were confirmed through STR validation analysis.…”

“…Among these, FDA‐approved drugs exist only for the MAPK pathway, with MEK inhibitors being FDA‐approved for unresectable BRAF ‐mutant cutaneous melanoma. Preclinical studies have demonstrated that MAPK signaling is required for the growth of uveal melanoma cell lines in vitro, with MEK inhibitors (MEKi) being found to have anti‐proliferative activity in the single‐agent setting (Ambrosini, Khanin, Carvajal, & Schwartz, ; Ambrosini et al, ; Cheng et al, , ; Faiao‐Flores et al, ). The therapeutic utility of MEKi have also been explored clinically in advanced uveal melanoma.…”

Uveal melanoma: progress in molecular biology and therapeutics

“…The MEK–HDAC inhibitor combination outperformed either agent alone, resulting in a long-term decrease in tumor growth in both subcutaneous and liver metastasis models. 204 In addition, Booth et al . have used PDX-derived UM cell lines to confirm that combining the HDAC inhibitor entinostat with neratinib, an inhibitor of human epidermal growth factor receptor 2 and epidermal growth factor receptor (EGFR) tyrosine kinases, exerts additive cytotoxic effects.…”

17‑AAG synergizes with Belinostat to exhibit a negative effect on the proliferation and invasion of MDA‑MB‑231 breast cancer cells

“…and deeper impact on the migration and invasion of cancer cells compared with various other genes. Previous studies have indicated the effect of HSP90 and HDAC6 (80,81) in regulating the function of the YAP/TAZ/TEAD complex. However, the detailed mechanism of how the TEAD genes affected MDA-MB-231 cell migration requires further research.…”