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

Somatic gain-of-function mutations of GNAQ and GNA11, which encode. subunits of heterotrimeric G alpha(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 G alpha(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 G alpha(q)/11 proteins and preferentially inhibited mitogenic ERK signaling rather than canonical phospholipase C beta(PLC beta) signaling driven by these oncogenes. Thereby, FR suppressed the proliferation of melanoma cells in culture and inhibited the growth of G alpha(q)-driven UM mouse xenografts in vivo. In contrast, FR did not affect tumor growth when xenografts carried mutated B-Raf(V600E) as the oncogenic driver. Because FR enabled suppression of malignant traits in cancer cells that are driven by activating mutations at codon 209 in G alpha(q)/11 proteins, we envision that similar approaches could be taken to blunt the signaling of non-G alpha(q)/11 G proteins.