PXD038023

PXD038023 is an original dataset announced via ProteomeXchange.

Title	High throughput chemogenetic drug screening reveals therapeutic vulnerabilities in the signaling circuitries underlying GNAQ-mutant uveal melanoma
Description	Uveal melanoma (UM) is the most prevalent cancer of the eye in adults, with a highly aggressive form of metastasis that is refractory to current therapies. UM is driven by aberrant activation of the Gαq pathway by hotspot activating mutation of GNAQ/GNA11, with few additional genetic aberrations. Despite this, there are limited effective targeted therapies currently available against the treatment of UM and mUM. Here, we performed a high-throughput chemogenetic drug screen in GNAQ-mutant UM contrasted with that of BRAF-mutant skin cutaneous melanoma, as a network chemical biology-based approach to identify therapeutic agents that target the mechanistic underpinnings driving UM. We observed strong genotype-driven drug sensitivities, and identified several drug classes with preferential activity against UM using a method termed Drug Set Enrichment Analysis (DSEA). Among them, we found an enrichment for PKC inhibitors, and identified one compound LXS-196, with the highest preferential activity against UM. Our investigation into the mechanism of action of LXS-196 revealed that in addition to inhibiting the Gq-ERK pathway, unlike other PKC inhibitors, this drug also reduced FAK activity, a recently identified mediator of non-canonical Gαq-driven oncogenic signaling. Kinome profiling revealed that LXS-196 acts as a multi-targeted kinase inhibitor, with high preference for PKC as well as PKN/PRK, the latter a poorly investigated AGC kinase that is activated directly by RhoA. This primes LXS-196 to target cell-essential pathways that drive tumor growth in UM by targeting both PKC, in addition to FAK. Moreover, we find that PKN is activated by GNAQ downstream from RhoA, thereby contributing to FAK stimulation. These findings expose a signaling vulnerability that can be targeted pharmacologically. Ultimately, dual PKC and PKN inhibition by LXS-196 acts synergistically with FAK inhibitors (FAKi) to halt UM growth and promote cytotoxic cell death in vitro and in preclinical metastatic mouse models, thus providing a highly translatable therapeutic multimodal precision strategy against mUM.
HostingRepository	PRIDE
AnnounceDate	2024-01-23
AnnouncementXML	Submission_2024-01-22_22:17:45.132.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Danielle Swaney
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2022-11-07 10:14:53	ID requested
⏵ 1	2024-01-22 22:17:46	announced

Arang N, Lubrano S, Ceribelli M, Rigiracciolo DC, Saddawi-Konefka R, Faraji F, Ramirez SI, Kim D, Tosto FA, Stevenson E, Zhou Y, Wang Z, Bogomolovas J, Molinolo AA, Swaney DL, Krogan NJ, Yang J, Coma S, Pachter JA, Aplin AE, Alessi DR, Thomas CJ, Gutkind JS, High-throughput chemogenetic drug screening reveals PKC-RhoA/PKN as a targetable signaling vulnerability in GNAQ-driven uveal melanoma. Cell Rep Med, 4(11):101244(2023) [pubmed]

10.1016/j.xcrm.2023.101244;

submitter keyword: cancer, uveal melanoma,APMS

Nevan Krogan
contact affiliation	UCSF
contact email	daniswan@gmail.com
lab head
Danielle Swaney
contact affiliation	UCSF
contact email	daniswan@gmail.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/01/PXD038023

PRIDE project URI

• PRIDE
  1. PXD038023
     1. Label: PRIDE project
     2. Name: High throughput chemogenetic drug screening reveals therapeutic vulnerabilities in the signaling circuitries underlying GNAQ-mutant uveal melanoma