Effects of Oncogenic Gαq and Gα11 Inhibition by FR900359 in Uveal Melanoma

  • Mol Cancer Res. 2019 Apr;17(4):963-973. doi: 10.1158/1541-7786.MCR-18-0574.
Dominic Lapadula  1 ,  Eduardo Farias  2  3  4 ,  Clinita E Randolph  1 ,  Timothy J Purwin  5 ,  Dougan McGrath  1 ,  Thomas H Charpentier  1 ,  Lihong Zhang  6 ,  Shihua Wu  6 ,  Mizue Terai  7 ,  Takami Sato  7 ,  Gregory G Tall  8 ,  Naiming Zhou  6 ,  Philip B Wedegaertner  1 ,  Andrew E Aplin  5 ,  Julio Aguirre-Ghiso  2  3  4 ,  Jeffrey L Benovic  9
Affiliations
  • 1. Department of Biochemistry and Molecular Biology, Cancer Cell Biology and Signaling Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
  • 2. Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 3. Department of Otolaryngology, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 4. Department of Oncological Sciences and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
  • 5. Department of Cancer Biology, Cancer Cell Biology and Signaling Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
  • 6. College of Life Sciences, Zhejiang University, Hangzhou, P.R. China.
  • 7. Department of Medical Oncology, Sidney Kimmel Medical College, Cancer Cell Biology and Signaling Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
  • 8. Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, Michigan.
  • 9. Department of Biochemistry and Molecular Biology, Cancer Cell Biology and Signaling Program, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania. [email protected].
PMID: 30567972 DOI: 10.1158/1541-7786.MCR-18-0574
Abstract

Uveal melanoma is the most common intraocular tumor in adults and often metastasizes to the liver, leaving patients with few options. Recurrent activating mutations in the G proteins, Gαq and Gα11, are observed in approximately 93% of all uveal melanomas. Although therapeutic intervention of downstream Gαq/11 targets has been unsuccessful in treating uveal melanoma, we have found that the Gαq/11 inhibitor, FR900359 (FR), effectively inhibits oncogenic Gαq/11 signaling in uveal melanoma cells expressing either mutant Gαq or Gα11. Inhibition of oncogenic Gαq/11 by FR results in cell-cycle arrest and induction of Apoptosis. Furthermore, colony formation is prevented by FR treatment of uveal melanoma cells in 3D-cell culture, providing promise for future in vivo studies. This suggests direct inhibition of activating Gαq/11 mutants may be a potential means of treating uveal melanoma. IMPLICATIONS: Oncogenic Gαq/11 inhibition by FR900359 may be a potential treatment option for those with uveal melanoma.

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