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

Cell Rep Med. 2023 Nov 21;4(11):101244. doi: 10.1016/j.xcrm.2023.101244. Epub 2023 Oct 18.

Abstract

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.

Keywords: FAK; GNAQ; PKC; PKN/PRK; chemogenetic drug screening; combination therapy; melanoma; precision medicine; synthetic lethality.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Drug Evaluation, Preclinical
  • GTP-Binding Protein alpha Subunits / genetics
  • GTP-Binding Protein alpha Subunits / metabolism
  • GTP-Binding Protein alpha Subunits, Gq-G11 / genetics
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • GTP-Binding Protein alpha Subunits, Gq-G11 / therapeutic use
  • Melanoma* / drug therapy
  • Melanoma* / genetics
  • Melanoma* / pathology
  • Mice
  • Protein Kinase Inhibitors / pharmacology
  • Skin Neoplasms*
  • Uveal Neoplasms* / drug therapy
  • Uveal Neoplasms* / genetics
  • Uveal Neoplasms* / metabolism

Substances

  • GTP-Binding Protein alpha Subunits
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Protein Kinase Inhibitors

Supplementary concepts

  • Uveal melanoma