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Principal Investigator: Andrew Eric Aplin
Organization: UNIVERSITY OF CALIFORNIA, SAN DIEGO
Fiscal Year: 2024
Award: $502,859
Funding agency: National Cancer Institute
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
Terms: <21+ years old><Address><Adult><Adult Human><Affect><CRISPR editing screen><CRISPR screen><CRISPR-based screen><CRISPR/Cas9 screen><Cancer Genes><Cancer-Promoting Gene><Cancers><Cell Body><Cell Communication and Signaling><Cell Death><Cell Line><Cell Signaling><Cell Surface Proteins><Cell Survival><Cell Viability><CellLine><Cells><Cellular Expansion><Cellular Growth><Cessation of life><Clinical><Clinical Trials><Combined Modality Therapy><Cutaneous Melanoma><Cytostatic Agents><Cytostatic Drugs><Cytostatics><Death><Development><Diagnosis><Disease><Disease remission><Disorder><Drug Combinations><Drug resistance><Drugs><Dysfunction><Event><Exposure to><Eye Cancer><FADK><FAK><FAK1><Family><Foundations><Frequencies><Functional disorder><Future><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G alpha q Protein><G-Protein-Coupled Receptors><G-Proteins><GAQ><GNAQ><GNAQ gene><GPCR><GTP Phosphohydrolases><GTP-Binding Proteins><GTP-Regulatory Proteins><GTPases><Galphaq Protein><Generalized Growth><Genetic Alteration><Genetic Change><Genetic analyses><Genetic defect><Genomics><Gq G-Protein><Gq Protein><Gq alpha Family G-Protein><Growth><Guanine Nucleotide Coupling Protein><Guanine Nucleotide Regulatory Proteins><Guanosine Triphosphate Phosphohydrolases><Guanosinetriphosphatases><Gαq Protein><Hepatic Neoplasm Secondary><Hepatic metastasis><Human><Intracellular Communication and Signaling><Intraocular Melanoma><Investigation><Link><Liver><Liver secondaries><Liver secondary cancer><Malignant Cutaneous Melanoma><Malignant Eye Neoplasm><Malignant Melanoma><Malignant Melanoma of Skin><Malignant Neoplasms><Malignant Ocular Neoplasm><Malignant Ocular Tumor><Malignant Tumor><Malignant Tumor of the Eye><Medication><Melanoma><Melanoma Cell><Melanoma Metastasis><Melanoma Skin><Melanoma patient><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Melanoma><Metastatic Neoplasm><Metastatic Neoplasm to the Liver><Metastatic Tumor><Metastatic Tumor to the Liver><Metastatic malignant neoplasm to liver><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Target><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Mutation><Nature><Neoplasm Metastasis><Oncogenes><Oncogenic><PTK2><PTK2 gene><Pathway interactions><Patients><Pharmaceutical Preparations><Physiologic><Physiological><Physiopathology><Play><Population><Position><Positioning Attribute><Precision therapeutics><Primary Lesion><Refractory><Relapse><Remission><Resistance><Risk><Role><Sampling><Secondary Neoplasm><Secondary Tumor><Signal Transduction><Signal Transduction Systems><Signaling><Skin><Specificity><Strains Cell Lines><System><Therapeutic><Tissue Growth><Toxic effect><Toxicities><Transforming Genes><Transmission><Tyrosine Phosphorylation><United States><Unresectable><Uveal Melanoma><Xenograft Model><adulthood><biological signal transduction><cancer cell genome><cancer genome><cancer metastasis><cancer type><cell growth><check point blocker><checkpoint blockers><chemotherapy><clinical predictors><clinical relevance><clinically relevant><clustered regularly interspaced short palindromic repeats screen><combination therapy><combined modality treatment><combined treatment><computational pipelines><cultured cell line><dermal melanoma><developmental><drug resistant><drug/agent><effective therapy><effective treatment><gene interaction><genetic analysis><genome mutation><guanosinetriphosphatase><hepatic body system><hepatic organ system><human disease><immune check point blocker><immune checkpoint blockers><in vivo><inhibitor><liver metastases><malignancy><malignant liver neoplasm, specified as secondary><malignant neoplasm of eye><metastasis in the liver><metastasis to the liver><metastasize to the liver><metastatic cancer to liver><metastatic liver><metastatic liver neoplasm><molecular phenotype><multi-modal therapy><multi-modal treatment><multi-modality><multidisciplinary><multimodality><mutant><necrocytosis><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><ontogeny><pathophysiology><pathway><pp125FAK><precision therapies><precision treatment><predictive biomarkers><predictive marker><predictive molecular biomarker><prevent><preventing><resistance to Drug><resistant><resistant to Drug><response to therapy><response to treatment><secondary liver malignancy><secondary malignant liver neoplasm><side effect><social role><synergism><therapeutic response><therapeutically effective><therapy response><transmission process><treatment response><treatment responsiveness><tumor><tumor cell metastasis><tumor genome><tumorigenic><uvea melanoma><xenograft transplant model><xenotransplant model>