Combined inhibition of Gα(q) and MEK enhances therapeutic efficacy in uveal melanoma Journal Article

Authors: Hitchman, T. D.; Bayshtok, G.; Ceraudo, E.; Moore, A. R.; Lee, C.; Jia, R.; Wang, N.; Pachai, M. R.; Shoushtari, A. N.; Francis, J. H.; Guan, Y.; Chen, J.; Chang, M. T.; Taylor, B. S.; Sakmar, T. P.; Huber, T.; Chi, P.; Chen, Y.
Article Title: Combined inhibition of Gα(q) and MEK enhances therapeutic efficacy in uveal melanoma
Abstract: Purpose: All uveal melanoma and a fraction of other melanoma subtypes are driven by activation of the G-protein alpha-q (Gaq) pathway. Targeting these melanomas has proven difficult despite advances in the molecular understanding of key driver signaling pathways in the disease pathogenesis. Inhibitors of Gaq have shown promising preclinical results, but their therapeutic activity in distinct Gaq 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 Gaq inhibition as a single agent and in combination with MEK inhibition. Results: We demonstrate that the Gaq 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 Gaq and MEK inhibition provides a promising therapeutic strategy and improved therapeutic window of broadly targeting Gaq in uveal melanoma. © 2020 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 27
Issue: 5
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2021-03-01
Start Page: 1476
End Page: 1490
Language: English
DOI: 10.1158/1078-0432.Ccr-20-2860
PROVIDER: scopus
PUBMED: 33229459
PMCID: PMC8086191
Notes: Article -- Export Date: 1 April 2021 -- Source: Scopus
Citation Impact
MSK Authors
  1. Yu Chen
    104 Chen
  2. Jasmine Helen Francis
    182 Francis
  3. Ping Chi
    116 Chi
  4. Barry Stephen Taylor
    236 Taylor
  5. Matthew   Chang
    28 Chang
  6. Amanda Roxanne Moore
    9 Moore
  7. Youxin   Guan
    11 Guan
  8. Cindy J Lee
    7 Lee
  9. Juliet Chen
    2 Chen
  10. Ruobing Jia
    1 Jia
  11. Naitao Wang
    1 Wang
  12. Mohini R. Pachai
    1 Pachai