PXD031346

PXD031346 is an original dataset announced via ProteomeXchange.

Title	Differential network analysis of ROS1 inhibitors reveals lorlatinib polypharmacology: Phosphotyrosine Profiling
Description	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 kinase assays, pharmacological probes and RNA interference 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.
HostingRepository	PRIDE
AnnounceDate	2024-04-05
AnnouncementXML	Submission_2024-04-05_09:15:16.862.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD031346
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	John Koomen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2022-01-30 14:46:50	ID requested
⏵ 1	2024-04-05 09:15:17	announced

10.6019/PXD031346;

10.1016/j.chembiol.2023.09.011;

Liao Y, Remsing Rix LL, Li X, Fang B, Izumi V, Welsh EA, Monastyrskyi A, Haura EB, Koomen JM, Doebele RC, Rix U, Differential network analysis of ROS1 inhibitors reveals lorlatinib polypharmacology through co-targeting PYK2. Cell Chem Biol, 31(2):284-297.e10(2024) [pubmed]

submitter keyword: polypharmacology, Tyrosine Kinase Inhibitors, phosphotyrosine,ROS1, Lung Cancer, Lorlatinib

Uwe Rix
contact affiliation	Moffitt Cancer Center Tampa, FL, USA
contact email	uwe.rix@moffitt.org
lab head
John Koomen
contact affiliation	Moffitt Cancer Center
contact email	john.koomen@moffitt.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD031346
     1. Label: PRIDE project
     2. Name: Differential network analysis of ROS1 inhibitors reveals lorlatinib polypharmacology: Phosphotyrosine Profiling