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

Autor(es):Mostrar menos -

Faiao-Flores, Fernanda ^[1] ; Emmons, Michael F. ^[1] ; Durante, Michael A. ^{[2, 3]} ; Kinose, Fumi ^[4] ; Saha, Biswarup ^[1] ; Fang, Bin ^[5] ; Koomen, John M. ^[5] ; Chellappan, Srikumar P. ^[1] ; Maria-Engler, Silvya Stuchi ^[6] ; Rix, Uwe ^[4] ; Licht, Jonathan D. ^[7] ; Harbour, J. William ^{[2, 3]} ; Smalley, Keiran S. M. ^[1]

Afiliação do(s) autor(es)

^[1] H Lee Moffitt Canc Ctr & Res Inst, Dept Tumor Biol, Tampa, FL - USA

^[2] Univ Miami, Miller Sch Med, Bascom Palmer Eye Inst, Sylvester Comprehens Canc Ctr, Miami, FL 33136 - USA

^[3] Univ Miami, Miller Sch Med, Interdisciplinary Stem Cell Inst, Miami, FL 33136 - USA

^[4] H Lee Moffitt Canc Ctr & Res Inst, Dept Drug Discovery, Tampa, FL - USA

^[5] H Lee Moffitt Canc Ctr & Res Inst, Dept Mol Oncol, Tampa, FL - USA

^[6] Univ Sao Paulo, Dept Clin Chem & Toxicol Anal, Sch Pharmaceut Sci, Sao Paulo - Brazil

^[7] Univ Florida, Dept Med, Div Hematol & Oncol, Hlth Canc Ctr, Gainesville, FL - USA

• Tipo de documento: Artigo Científico
• Fonte: Clinical Cancer Research; v. 25, n. 18, p. 5686-5701, SEP 2019.
• Citações Web of Science: 4

Resumo

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 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. (AU)

• Processo FAPESP: 13/05172-4 - Impacto das proteínas da transição epitélio-mesênquima em melanoma quimioresistente ao vemurabenibe
• Beneficiário: Fernanda Faião Flores
• Linha de fomento: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 15/10821-7 - Efeito da inibição de Hsp90 nas vias de escape terapêutico de melanoma BRAF-mutado
• Beneficiário: Fernanda Faião Flores
• Linha de fomento: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado