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

Abstract

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.

Heterotrimeric Gq proteins as therapeutic targets?

“…4A) (116). Thus, both mutants differ in their oncogenic properties because R183C prefers GTP over GDP yet still responds to receptor stimulation, whereas Q209L/P is largely, if not entirely, uncoupled from activation by upstream acting GPCRs (9,110,(116)(117)(118) (Fig. 4A).…”

“…Regardless, G q inhibition with FR provided the proof of principle for a novel route to reprogram a range of skin melanoma cells-those that are instructed by G q to proliferate-to a less aggressive phenotype (11). Because mutant G␣ q or G␣ 11 proteins are found in only 4% of skin melanoma but in 90% of uveal melanoma, it was not surprising to observe researchers turn to the study of FR in cell lines from uveal melanoma tumors: four independent studies on similar subject matter emerged within just a 6-month time frame (97,100,110,111).…”

“…FR and YM are precisely such GDIs, viewed as unsuited for manipulating the oncogenic signaling driven by GTPase-deficient G␣ q proteins for experimental or therapeutic purposes. However, FR in particular has shown convincing efficacy against UM cancer cells as brought to focus by four independent studies (97,100,110,111). How come?…”

“…Yet, mutation-specific inhibitors for active G␣ have not been reported to date, and, moreover, G␣ GTP antagonizing agents will likely also block the signaling of WT GTPases in that only a low dosage might afford a therapeutic window for targeted (preferential) inhibition of the oncogenic over the WT G␣ GTP pool. In light of these considerations and the current absence of X-ray structural information on GTPase-deficient G␣ q , the recent successes to target mutationally activated G q with FR in uveal melanoma must be viewed as a considerable breakthrough (97,110,111). Guanine nucleotide dissociation inhibitors of heterotrimeric G proteins such as FR may therefore evolve to be cornerstones of "anti-G␣ GTP therapies," given their proven capacity to shift the nucleotide preference of G␣ proteins toward the GDP-bound inactive state (Fig.…”

Recent achievements in developing selective Gq inhibitors

“…Finally, the therapeutic potential for G q selective inhibitors has been described in other reviews. 23,58 YM-254890 and FR900359 have a potential use in cancer treatment, especially as FR900359 was found to force melanoma cells into differentiation while simultaneously inhibiting migration, 56 and very recently, been found to suppress proliferation 107 and promote cell cycle arrest and eventual cell death 108 in uveal melanoma. YM-254890 has also been shown to selectively inhibit the oncogenic Gα 11 -mediated signaling where the two most-prevalent Gα 11 mutants, Q209L and R183C, which are found in more than 2% of all human cancers, were introduced.…”