High-throughput chemogenetic drug screening reveals PKC-RhoA/PKN as a targetable signaling vulnerability in GNAQ-driven uveal melanoma

TY - JOUR

T1 - High-throughput chemogenetic drug screening reveals PKC-RhoA/PKN as a targetable signaling vulnerability in GNAQ-driven uveal melanoma

AU - Arang, Nadia

AU - Lubrano, Simone

AU - Ceribelli, Michele

AU - Rigiracciolo, Damiano C.

AU - Saddawi-Konefka, Robert

AU - Faraji, Farhoud

AU - Ramirez, Sydney I.

AU - Kim, Daehwan

AU - Tosto, Frances A.

AU - Stevenson, Erica

AU - Zhou, Yuan

AU - Wang, Zhiyong

AU - Bogomolovas, Julius

AU - Molinolo, Alfredo A.

AU - Swaney, Danielle L.

AU - Krogan, Nevan J.

AU - Yang, Jing

AU - Coma, Silvia

AU - Pachter, Jonathan A.

AU - Aplin, Andrew E.

AU - Alessi, Dario R.

AU - Thomas, Craig J.

AU - Gutkind, J. Silvio

N1 - Copyright: © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2023/11/21

Y1 - 2023/11/21

N2 - Uveal melanoma (UM) is the most prevalent cancer of the eye in adults, driven by activating mutation of GNAQ/GNA11; however, there are limited therapies against UM and metastatic UM (mUM). Here, we perform a high-throughput chemogenetic drug screen in GNAQ-mutant UM contrasted with BRAF-mutant cutaneous melanoma, defining the druggable landscape of these distinct melanoma subtypes. Across all compounds, darovasertib demonstrates the highest preferential activity against UM. Our investigation reveals that darovasertib potently inhibits PKC as well as PKN/PRK, an AGC kinase family that is part of the "dark kinome." We find that downstream of the Gαq-RhoA signaling axis, PKN converges with ROCK to control FAK, a mediator of non-canonical Gαq-driven signaling. Strikingly, darovasertib synergizes with FAK inhibitors to halt UM growth and promote cytotoxic cell death in vitro and in preclinical metastatic mouse models, thus exposing a signaling vulnerability that can be exploited as a multimodal precision therapy against mUM.

AB - Uveal melanoma (UM) is the most prevalent cancer of the eye in adults, driven by activating mutation of GNAQ/GNA11; however, there are limited therapies against UM and metastatic UM (mUM). Here, we perform a high-throughput chemogenetic drug screen in GNAQ-mutant UM contrasted with BRAF-mutant cutaneous melanoma, defining the druggable landscape of these distinct melanoma subtypes. Across all compounds, darovasertib demonstrates the highest preferential activity against UM. Our investigation reveals that darovasertib potently inhibits PKC as well as PKN/PRK, an AGC kinase family that is part of the "dark kinome." We find that downstream of the Gαq-RhoA signaling axis, PKN converges with ROCK to control FAK, a mediator of non-canonical Gαq-driven signaling. Strikingly, darovasertib synergizes with FAK inhibitors to halt UM growth and promote cytotoxic cell death in vitro and in preclinical metastatic mouse models, thus exposing a signaling vulnerability that can be exploited as a multimodal precision therapy against mUM.

KW - melanoma

KW - GNAQ

KW - chemogenetic drug screening

KW - PKC

KW - PKN/PRK

KW - FAK

KW - synthetic lethality

KW - combination therapy

KW - precision medicine

U2 - 10.1016/j.xcrm.2023.101244

DO - 10.1016/j.xcrm.2023.101244

M3 - Article

C2 - 37858338

SN - 2666-3791

VL - 4

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 11

M1 - 101244

ER -