Differential network analysis of ROS1 inhibitors reveals lorlatinib polypharmacology through co-targeting PYK2
Copyright © 2023 Elsevier Ltd. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:31 |
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| Enthalten in: |
Cell chemical biology - 31(2024), 2 vom: 15. Feb., Seite 284-297.e10 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Liao, Yi [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 19.02.2024 Date Revised 09.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.chembiol.2023.09.011 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 500 | |a Date Revised 09.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier Ltd. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Lorlatinib | |
| 650 | 4 | |a PYK2 | |
| 650 | 4 | |a ROS1 | |
| 650 | 4 | |a SRC | |
| 650 | 4 | |a chemoproteomics | |
| 650 | 4 | |a network analysis | |
| 650 | 4 | |a non-small cell lung cancer | |
| 650 | 4 | |a phosphoproteomics | |
| 650 | 4 | |a polypharmacology | |
| 650 | 4 | |a synergy | |
| 650 | 7 | |a Aminopyridines |2 NLM | |
| 650 | 7 | |a Anaplastic Lymphoma Kinase |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 650 | 7 | |a Focal Adhesion Kinase 2 |2 NLM | |
| 650 | 7 | |a EC 2.7.10.2 |2 NLM | |
| 650 | 7 | |a Lactams |2 NLM | |
| 650 | 7 | |a Lactams, Macrocyclic |2 NLM | |
| 650 | 7 | |a lorlatinib |2 NLM | |
| 650 | 7 | |a OSP71S83EU |2 NLM | |
| 650 | 7 | |a Protein Kinase Inhibitors |2 NLM | |
| 650 | 7 | |a Protein-Tyrosine Kinases |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins |2 NLM | |
| 650 | 7 | |a Pyrazoles |2 NLM | |
| 650 | 7 | |a ROS1 protein, human |2 NLM | |
| 650 | 7 | |a EC 2.7.10.1 |2 NLM | |
| 700 | 1 | |a Remsing Rix, Lily L |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Xueli |e verfasserin |4 aut | |
| 700 | 1 | |a Fang, Bin |e verfasserin |4 aut | |
| 700 | 1 | |a Izumi, Victoria |e verfasserin |4 aut | |
| 700 | 1 | |a Welsh, Eric A |e verfasserin |4 aut | |
| 700 | 1 | |a Monastyrskyi, Andrii |e verfasserin |4 aut | |
| 700 | 1 | |a Haura, Eric B |e verfasserin |4 aut | |
| 700 | 1 | |a Koomen, John M |e verfasserin |4 aut | |
| 700 | 1 | |a Doebele, Robert C |e verfasserin |4 aut | |
| 700 | 1 | |a Rix, Uwe |e verfasserin |4 aut | |
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