Affordable Access

Publisher Website

Differential network analysis of ROS1 inhibitors reveals lorlatinib polypharmacology through co-targeting PYK2.

Authors
  • Liao, Yi1
  • Remsing Rix, Lily L1
  • Li, Xueli1
  • Fang, Bin2
  • Izumi, Victoria2
  • Welsh, Eric A3
  • Monastyrskyi, Andrii4
  • Haura, Eric B5
  • Koomen, John M6
  • Doebele, Robert C7
  • Rix, Uwe8
  • 1 Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 2 Proteomics and Metabolomics Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 3 Biostatistics and Bioinformatics Shared Resource, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 4 Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida, Tampa, FL 33620, USA.
  • 5 Department of Thoracic Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 6 Department of Oncologic Sciences, University of South Florida, Tampa, FL 33620, USA; Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.
  • 7 Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
  • 8 Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA; Department of Oncologic Sciences, University of South Florida, Tampa, FL 33620, USA. Electronic address: [email protected].
Type
Published Article
Journal
Cell chemical biology
Publication Date
Feb 15, 2024
Volume
31
Issue
2
Identifiers
DOI: 10.1016/j.chembiol.2023.09.011
PMID: 37848034
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Multiple tyrosine kinase inhibitors (TKIs) are often developed for the same indication. However, their relative overall efficacy is frequently incompletely understood and they may harbor unrecognized targets that cooperate with the intended target. We compared several ROS1 TKIs for inhibition of ROS1-fusion-positive lung cancer cell viability, ROS1 autophosphorylation and kinase activity, which indicated disproportionately higher cellular potency of one TKI, lorlatinib. Quantitative chemical and phosphoproteomics across four ROS1 TKIs and differential network analysis revealed that lorlatinib uniquely impacted focal adhesion signaling. Functional validation using pharmacological probes, RNA interference, and CRISPR-Cas9 knockout uncovered a polypharmacology mechanism of lorlatinib by dual targeting ROS1 and PYK2, which form a multiprotein complex with SRC. Rational multi-targeting of this complex by combining lorlatinib with SRC inhibitors exhibited pronounced synergy. Taken together, we show that systems pharmacology-based differential network analysis can dissect mixed canonical/non-canonical polypharmacology mechanisms across multiple TKIs enabling the design of rational drug combinations. Copyright © 2023 Elsevier Ltd. All rights reserved.

Report this publication

Statistics

Seen <100 times