# Targeting Systems Vulnerabilities in the Gαq/GNAQ Oncogenic Signaling Circuitry: New Precision Therapies for Uveal Melanoma

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $535,362

## Abstract

Targeting Systems Vulnerabilities in the Gαq/GNAQ Oncogenic Signaling Circuitry: New Precision
Therapies for Uveal Melanoma
G protein-coupled receptors (GPCRs) represent the largest family of cell surface proteins involved in signal
transmission. GPCRs play key physiological roles and their dysfunction contributes to some of the most prevalent
human diseases, making them the target of >25% of all therapeutic drugs. Strikingly, our recent analysis of
human cancer genomes revealed an unanticipated high frequency of mutations in G proteins and GPCRs in
most tumor types. Indeed, nearly 30% of human cancers harbor mutations in GPCRs or G proteins. While their
tumorigenic potential is under investigation, activating mutations in GNAQ and GNA11 (herein referred as GNAQ
oncogenes, which encode GTPase deficient and constitutively active Gαq proteins), were identified in ~93% of
uveal melanoma (UM) and 4% of skin cutaneous melanoma (SKCM), respectively, where they act as oncogenic
drivers. UM is the most common primary cancer of the eye in adults, affecting more than 2,500 patients each
year in the US alone, nearly 50% of which will die from liver metastasis. To date, there are no effective therapeutic
options to treat metastatic UM disease (mUM). We recently demonstrated that YAP activation is central to UM
growth and uncovered a novel direct link between Gαq-FAK driven tyrosine phosphorylation networks and YAP
activation. Our central hypothesis is that this signaling specificity may represent a systems vulnerability that can
be exploited for the development of new precision therapies for mUM. Our overall hypothesis is that our proposed
studies targeting FAK, which acts downstream from Gαq, and its compensatory (resistance) or synthetic lethal
(sensitizing) mechanisms will provide an oncogene-specific therapeutic approach for advanced and mUM,
resulting in increased antitumor activity with lower toxicities and fewer side effects. Ultimately, our premise is
that FAK is an integral part of the GNAQ oncogenic pathway and that in turn, FAK blockade with clinically relevant
FAK inhibitors (FAKi) may represent a precision therapeutic approach for the treatment of mUM, alone or as part
or as part of novel signal transduction-based precision co-targeting strategies. This will be investigated in 3 aims:
Aim 1: To exploit GNAQ-synthetic lethal and gene interaction networks to expose systems vulnerabilities
resulting in UM cell death as a precision therapeutic approach to treat mUM. Aim 2. To establish the therapeutic
potential of co-targeting the Gαq-FAK regulated pathway in vivo. Aim 3. Characterization of FAKi/MEKi tolerant
persister populations and mechanisms of acquired resistance

## Key facts

- **NIH application ID:** 10369699
- **Project number:** 5R01CA257505-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Andrew Eric Aplin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $535,362
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10369699

## Citation

> US National Institutes of Health, RePORTER application 10369699, Targeting Systems Vulnerabilities in the Gαq/GNAQ Oncogenic Signaling Circuitry: New Precision Therapies for Uveal Melanoma (5R01CA257505-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10369699. Licensed CC0.

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