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Translational Cancer Mechanisms and Therapy

Combined Inhibition of Gαq and MEK Enhances Therapeutic Efficacy in Uveal Melanoma

Tyler D. Hitchman, Gabriella Bayshtok, Emilie Ceraudo, Amanda R. Moore, Cindy Lee, Ruobing Jia, Naitao Wang, Mohini R. Pachai, Alexander N. Shoushtari, Jasmine H. Francis, Youxin Guan, Juliet Chen, Matthew T. Chang, Barry S. Taylor, Thomas P. Sakmar, Thomas Huber, Ping Chi and Yu Chen
Tyler D. Hitchman
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York.
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Gabriella Bayshtok
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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Emilie Ceraudo
3Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, New York.
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  • ORCID record for Emilie Ceraudo
Amanda R. Moore
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
4Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York.
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Cindy Lee
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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Ruobing Jia
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
5Department of Ophthalmology, Ninth People’s Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, P.R. China.
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Naitao Wang
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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Mohini R. Pachai
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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Alexander N. Shoushtari
6Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
7Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York.
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  • ORCID record for Alexander N. Shoushtari
Jasmine H. Francis
8Opthalmic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
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  • ORCID record for Jasmine H. Francis
Youxin Guan
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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Juliet Chen
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
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  • ORCID record for Juliet Chen
Matthew T. Chang
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
9Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
10Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California.
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Barry S. Taylor
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
9Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
11Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Thomas P. Sakmar
3Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, New York.
12Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Solna, Sweden.
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Thomas Huber
3Laboratory of Chemical Biology and Signal Transduction, The Rockefeller University, New York, New York.
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Ping Chi
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York.
4Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York.
6Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
7Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York.
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  • For correspondence: cheny1@mskcc.org chip@mskcc.org
Yu Chen
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York.
4Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York.
6Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
7Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, New York, New York.
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  • For correspondence: cheny1@mskcc.org chip@mskcc.org
DOI: 10.1158/1078-0432.CCR-20-2860
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Abstract

Purpose: All uveal melanoma and a fraction of other melanoma subtypes are driven by activation of the G-protein alpha-q (Gαq) pathway. Targeting these melanomas has proven difficult despite advances in the molecular understanding of key driver signaling pathways in the disease pathogenesis. Inhibitors of Gαq have shown promising preclinical results, but their therapeutic activity in distinct Gαq mutational contexts and in vivo have remained elusive.

Experimental Design: We used an isogenic melanocytic cellular system to systematically examine hotspot mutations in GNAQ (e.g., G48V, R183Q, Q209L) and CYSLTR2 (L129Q) found in human uveal melanoma. This cellular system and human uveal melanoma cell lines were used in vitro and in in vivo xenograft studies to assess the efficacy of Gαq inhibition as a single agent and in combination with MEK inhibition.

Results: We demonstrate that the Gαq inhibitor YM-254890 inhibited downstream signaling and in vitro growth in all mutants. In vivo, YM-254890 slowed tumor growth but did not cause regression in human uveal melanoma xenografts. Through comprehensive transcriptome analysis, we observed that YM-254890 caused inhibition of the MAPK signaling with evidence of rebound by 24 hours and combination treatment of YM-254890 and a MEK inhibitor led to sustained MAPK inhibition. We further demonstrated that the combination caused synergistic growth inhibition in vitro and tumor shrinkage in vivo.

Conclusions: These data suggest that the combination of Gαq and MEK inhibition provides a promising therapeutic strategy and improved therapeutic window of broadly targeting Gαq in uveal melanoma.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2021;XX:XX–XX

  • Received July 21, 2020.
  • Revision received November 3, 2020.
  • Accepted November 18, 2020.
  • Published first November 23, 2020.
  • ©2020 American Association for Cancer Research.

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This OnlineFirst version was published on January 8, 2021
doi: 10.1158/1078-0432.CCR-20-2860

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Combined Inhibition of Gαq and MEK Enhances Therapeutic Efficacy in Uveal Melanoma
Tyler D. Hitchman, Gabriella Bayshtok, Emilie Ceraudo, Amanda R. Moore, Cindy Lee, Ruobing Jia, Naitao Wang, Mohini R. Pachai, Alexander N. Shoushtari, Jasmine H. Francis, Youxin Guan, Juliet Chen, Matthew T. Chang, Barry S. Taylor, Thomas P. Sakmar, Thomas Huber, Ping Chi and Yu Chen
Clin Cancer Res January 8 2021 DOI: 10.1158/1078-0432.CCR-20-2860

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Combined Inhibition of Gαq and MEK Enhances Therapeutic Efficacy in Uveal Melanoma
Tyler D. Hitchman, Gabriella Bayshtok, Emilie Ceraudo, Amanda R. Moore, Cindy Lee, Ruobing Jia, Naitao Wang, Mohini R. Pachai, Alexander N. Shoushtari, Jasmine H. Francis, Youxin Guan, Juliet Chen, Matthew T. Chang, Barry S. Taylor, Thomas P. Sakmar, Thomas Huber, Ping Chi and Yu Chen
Clin Cancer Res January 8 2021 DOI: 10.1158/1078-0432.CCR-20-2860
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Clinical Cancer Research
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