# Targeting G alpha q/11 in Uveal Melanoma

> **NIH NIH F31** · THOMAS JEFFERSON UNIVERSITY · 2020 · $45,520

## Abstract

PROJECT SUMMARY/ABSTRACT
Uveal melanoma (UM) is the most common intraocular tumor in adults and accounts for approximately 5% of
all melanomas. UM metastasizes primarily to the liver in 50% of patients, and currently there are no suitable
treatment options. In contrast to most cutaneous melanomas, which contain mutations in BRAF or NRAS,
~90% of all uveal melanomas contain activating mutations in either GNAQ or GNA11, which code for the Gαq
and Gα11 subunits of heterotrimeric G proteins. These two proteins are 90% homologous at the amino acid
level and stimulate common signaling pathways. The activating mutations are almost always seen at the Q209
or R183 residues and render Gαq/11 constitutively active when bound to GTP due to the loss of its intrinsic
GTPase activity. Introduction of the GNAQ-Q209L mutant, but not wild-type GNAQ, into human or mouse
melanocytes results in anchorage-independent growth and gives rise to heavily pigmented tumors in vivo.
Gαq/11 is involved in many downstream signaling pathways and its constitutive activity in UM leads to an
increase in the activation of MAPK, Akt and the small GTPases RhoA and Rac1, which stimulates the
transcription of growth promoting genes. We believe that it would be advantageous to directly inhibit oncogenic
Gαq/11 and prevent the activation of these various cell proliferating pathways. To this end, we have tested the
compound QIC, known to specifically inhibit wild type Gαq/11, and found that is also capable of inhibiting
oncogenic Gαq/11 found in UM. Based on these results, we hypothesize that we can use Gαq/11 inhibitors
such as QIC to provide a better mechanistic understanding of the role that oncogenic Gαq/11 plays in UM. To
test this hypothesis, we will: 1) further characterize the mechanism by which Gαq/11 specific inhibitors inhibit
oncogenic Gαq/11 proteins in vitro; 2) assess the effects of Gαq/11 inhibition on downstream signaling in uveal
melanoma cells; and 3) determine the effect of Gαq/11 inhibition on uveal melanoma cell growth and migration.
Taken together, these studies will enable a better mechanistic understanding of the role of Gαq/11 in uveal
melanoma and set the stage for the use of Gαq/11 inhibitors in animal models.

## Key facts

- **NIH application ID:** 9841922
- **Project number:** 5F31CA225064-03
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Dominic Lapadula
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 5
- **Project period:** 2018-01-15 → 2021-01-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841922

## Citation

> US National Institutes of Health, RePORTER application 9841922, Targeting G alpha q/11 in Uveal Melanoma (5F31CA225064-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9841922. Licensed CC0.

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