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Direct targeting of Gαq and Gα11 oncoproteins in cancer cells
Suvi Annala1, Xiaodong Feng2, Naveen Shridhar3
1Molecular, Cellular and Pharmacobiology Section, Institute for Pharmaceutical Biology, University of Bonn, Nussallee 6, 53115 Bonn, Germany.
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.
Insights
A novel cyclic depsipeptide, FR900359 (FR), directly targets oncogenic Gαq/11 proteins in uveal melanoma. FR inhibits cancer cell proliferation and tumor growth by suppressing key signaling pathways, offering a new therapeutic avenue.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Uveal melanoma (UM) frequently harbors GNAQ/GNA11 mutations, leading to constitutively active Gαq/11 proteins.
- Current UM treatments lack targeted therapies against these specific oncoproteins.
- Oncogenic Gαq/11 proteins exhibit reduced GTP hydrolysis, maintaining an active state.
Purpose of the Study:
- To identify and evaluate a direct inhibitor of oncogenic Gαq/11 proteins.
- To assess the efficacy of FR900359 (FR) in preclinical models of uveal melanoma.
- To investigate the downstream signaling effects of FR on cancer cells.
Main Methods:
- Direct interaction studies between FR900359 and Gαq/11 proteins.
- Assessment of FR's impact on ERK and phospholipase Cβ (PLCβ) signaling pathways.
- In vitro proliferation assays of melanoma cell lines.
- In vivo efficacy studies using Gαq-driven UM mouse xenografts.
Main Results:
- FR900359 directly binds to GTPase-deficient Gαq/11 proteins.
- FR preferentially inhibits mitogenic ERK signaling over PLCβ signaling.
- FR suppresses melanoma cell proliferation in culture.
- FR inhibits the growth of Gαq-driven UM xenografts in vivo.
- FR showed no effect on B-RafV600E-driven xenografts.
Conclusions:
- FR900359 is a potent inhibitor of Gαq/11-driven oncogenic signaling in uveal melanoma.
- FR demonstrates therapeutic potential by suppressing tumor growth and proliferation.
- Targeting Gαq/11 signaling with agents like FR represents a promising strategy for UM treatment.
- The findings suggest potential for similar approaches against other G protein-driven cancers.
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