1. Direct targeting of Gα q and Gα 11 oncoproteins in cancer cells.
- Author
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Annala S, Feng X, Shridhar N, Eryilmaz F, Patt J, Yang J, Pfeil EM, Cervantes-Villagrana RD, Inoue A, Häberlein F, Slodczyk T, Reher R, Kehraus S, Monteleone S, Schrage R, Heycke N, Rick U, Engel S, Pfeifer A, Kolb P, König G, Bünemann M, Tüting T, Vázquez-Prado J, Gutkind JS, Gaffal E, and Kostenis E
- Subjects
- Animals, Cell Line, Tumor, Depsipeptides chemistry, HEK293 Cells, Humans, Mice, Mice, Inbred NOD, Mice, SCID, Xenograft Model Antitumor Assays, Depsipeptides pharmacology, Drug Delivery Systems, GTP-Binding Protein alpha Subunits antagonists & inhibitors, GTP-Binding Protein alpha Subunits genetics, GTP-Binding Protein alpha Subunits metabolism, GTP-Binding Protein alpha Subunits, Gq-G11 antagonists & inhibitors, GTP-Binding Protein alpha Subunits, Gq-G11 genetics, GTP-Binding Protein alpha Subunits, Gq-G11 metabolism, Gain of Function Mutation, Melanoma drug therapy, Melanoma enzymology, Melanoma genetics, Melanoma pathology, Neoplasm Proteins antagonists & inhibitors, Neoplasm Proteins genetics, Neoplasm Proteins metabolism, Uveal Neoplasms drug therapy, Uveal Neoplasms enzymology, Uveal Neoplasms genetics, Uveal Neoplasms pathology
- Abstract
Somatic gain-of-function mutations of GNAQ and GNA11 , which encode α subunits of heterotrimeric Gα
q/11 proteins, occur in about 85% of cases of uveal melanoma (UM), the most common cancer of the adult eye. Molecular therapies to directly target these oncoproteins are lacking, and current treatment options rely on radiation, surgery, or inhibition of effector molecules downstream of these G proteins. A hallmark feature of oncogenic Gαq/11 proteins is their reduced intrinsic rate of hydrolysis of guanosine triphosphate (GTP), which results in their accumulation in the GTP-bound, active state. Here, we report that the cyclic depsipeptide FR900359 (FR) directly interacted with GTPase-deficient Gαq/11 proteins and preferentially inhibited mitogenic ERK signaling rather than canonical phospholipase Cβ (PLCβ) signaling driven by these oncogenes. Thereby, FR suppressed the proliferation of melanoma cells in culture and inhibited the growth of Gαq -driven UM mouse xenografts in vivo. In contrast, FR did not affect tumor growth when xenografts carried mutated B-RafV600E as the oncogenic driver. Because FR enabled suppression of malignant traits in cancer cells that are driven by activating mutations at codon 209 in Gαq/11 proteins, we envision that similar approaches could be taken to blunt the signaling of non-Gαq/11 G proteins., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2019
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