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Differential network analysis of ROS1 inhibitors reveals lorlatinib polypharmacology through co-targeting PYK2.
- Source :
-
Cell chemical biology [Cell Chem Biol] 2024 Feb 15; Vol. 31 (2), pp. 284-297.e10. Date of Electronic Publication: 2023 Oct 16. - Publication Year :
- 2024
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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.<br />Competing Interests: Declaration of interests R.C.D. is an employee and shareholder of Rain Oncology and reports licensing fees from Voronoi, Takeda, Loxo@Lilly, Foundation Medicine, Histocyte, Black Diamond, and ThermoFisher. JMK reports support from Bristol-Myers Squibb on an unrelated project. E.B.H. serves in a consulting or advisory role to Amgen, Ellipses Pharma, Janssen Oncology, Janssen Research & Development and Revolution Medicines; reports research funding (paid to his institution) from AstraZeneca, Genentech, Incyte, Janssen, Novartis, Revolution Medicines and Spectrum Pharmaceuticals; and reports patents, royalties or other intellectual property from ProteinProtein Interactions as Biomarkers Patent.<br /> (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Subjects :
- Humans
Aminopyridines pharmacology
Anaplastic Lymphoma Kinase genetics
Focal Adhesion Kinase 2 antagonists & inhibitors
Lactams, Macrocyclic
Polypharmacology
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins
Carcinoma, Non-Small-Cell Lung drug therapy
Lactams
Lung Neoplasms drug therapy
Protein-Tyrosine Kinases antagonists & inhibitors
Pyrazoles
Subjects
Details
- Language :
- English
- ISSN :
- 2451-9448
- Volume :
- 31
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cell chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 37848034
- Full Text :
- https://doi.org/10.1016/j.chembiol.2023.09.011