Direct targeting of Gα q and Gα 11 oncoproteins in cancer cells

Suvi Annala, Xiaodong Feng, Naveen Shridhar, Funda Eryilmaz, Julian Patt, Ju Hee Yang, Eva M. Pfeil, Rodolfo Daniel Cervantes-Villagrana, Asuka Inoue, Felix Häberlein, Tanja Slodczyk, Raphael Reher, Stefan Kehraus, Stefania Monteleone, Ramona Schrage, Nina Heycke, Ulrike Rick, Sandra Engel, Alexander Pfeifer, Peter KolbGabriele König, Moritz Bünemann, Thomas Tüting, José Vázquez-Prado, J. Silvio Gutkind, Evelyna Gaffal, Evi Kostenis

Research output: Contribution to journalArticlepeer-review

27 Citations (Scopus)

Abstract

Somatic gain-of-function mutations of GNAQ and GNA11, which encode ? 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 Gα q/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 Gα q / 11 proteins and preferentially inhibited mitogenic ERK signaling rather than canonical phospholipase C? (PLC?) signaling driven by these oncogenes. Thereby, FR suppressed the proliferation of melanoma cells in culture and inhibited the growth of Gα q-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 Gα q / 11 proteins, we envision that similar approaches could be taken to blunt the signaling of non-Gα q / 11 G proteins.

Original languageEnglish
Article numbereaau5948
JournalScience Signaling
Volume12
Issue number573
DOIs
Publication statusPublished - 2019

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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