Direct targeting of Gαq and Gα11 oncoproteins in cancer cells

Targeting uveal melanomaUveal melanoma (UM) is a common cancer of the eye, and about half of patients with UM develop metastatic disease. Although most cases of UM are driven by constitutively active mutants of the G protein α subunits Gαq and Gα11, therapies that target signaling pathways downstream of these oncogenic drivers have been unsuccessful. Annala et al. provide further evidence of the ability of the cyclic depsipeptide FR900359 (FR) to inhibit oncogenic Gαq/11 signaling in UM cell lines in vitro, particularly by blocking the mitogenic ERK pathway. Furthermore, FR reduced mutant Gαq–driven UM tumor growth in a mouse xenograft model, suggesting that FR or similar compounds should be further investigated for directly targeting oncogenic Gαq/11 proteins in patients with UM.Somatic gain-of-function mutations of GNAQ and GNA11, which encode α subunits of heterotrimeric Gαq/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.