TY - JOUR
T1 - HDAC inhibition enhances the in vivo efficacy of MEK inhibitor therapy in uveal melanoma
AU - Faião-Flores, Fernanda
AU - Emmons, Michael F.
AU - Durante, Michael A.
AU - Kinose, Fumi
AU - Saha, Biswarup
AU - Fang, Bin
AU - Koomen, John M.
AU - Chellappan, Srikumar P.
AU - Maria-Engler, Silvya Stuchi
AU - Rix, Uwe
AU - Licht, Jonathan D.
AU - Harbour, J. William
AU - Smalley, Keiran S.M.
N1 - Funding Information:
J.D. Licht reports receiving commercial research grants from Celgene. J.W. Harbour holds ownership interest (including patents) in Castle Biosciences and is a consultant/advisory board member for Castle Biosciences, Aura Biosciences, and Immunocore. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
The authors would like to thank Dr. Manali Phadke for technical assistance and support. This work is supported by the Bankhead-Coley Program of the State of Florida 7BC05, and the NIH R21 CA216756. It has been also supported, in part, by the SAIL Core Facility, the IRAT Core Facility, the Flow Cytometry Core Facility, the Analytic Microscopy Core Facility, the Proteomics and Meta-bolomics Core Facility, the Molecular Genomics Core and the Tissue Core Facility at the H. Lee Moffitt Cancer Center & Research Institute (Tampa, FL), an NCI designated Comprehensive Cancer Center (P30-CA076292). This work has also been supported, in part, by Fapesp (grant no. 2013/05172-4 and 2015/ 10821-7).
PY - 2019/9/15
Y1 - 2019/9/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-18-3382
DO - 10.1158/1078-0432.CCR-18-3382
M3 - Article
C2 - 31227503
AN - SCOPUS:85071547986
VL - 25
SP - 5686
EP - 5701
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 18
ER -