PXD005536-2

PXD005536 is an original dataset announced via ProteomeXchange.

Title	Quantitative phosphoproteomic analysis of acquired drug resistance to pazopanib and dasatinib
Description	Acquired drug resistance and tumour relapse impacts the majority of patients being treated with tyrosine kinase inhibitors (TKIs) and remains a key challenge in modern anti-cancer therapy. The lack of clinically effective therapeutic strategies to overcome drug resistance represents a significant unmet need. Understanding the signalling pathways that drive drug resistance will facilitate the development of new salvage therapies to effectively treat patients with secondary TKI resistance. In this study, we utilise quantitative mass spectrometry to characterise the global phosphoproteomic alterations that accompany the acquisition of resistance to two FDA-approved multi-target TKIs, pazopanib and dasatinib, in the A204 rhabdoid tumour cell line. Our analysis finds that only a limited fraction of the quantified phosphoproteome (<10%) is altered upon the acquisition of drug resistance with pazopanib resistant cells displaying elevated phosphorylation levels in cytoskeletal regulatory pathways and dasatinib resistant cells showing an upregulation of components of the insulin receptor/IGF1-R signalling pathway. Drug response profiling with a targeted panel of small molecule inhibitors rediscovers several previously reported vulnerabilities associated with pazopanib and dasatinib resistance and identifies a new dependency to the second generation HSP90 inhibitor NVP-AUY-922. This study provides a useful resource detailing the candidate signalling determinants of acquired TKI resistance; and reveals a therapeutic approach of inhibiting HSP90 function as a means of salvage therapy to overcome pazopanib and dasatinib resistance.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_04:38:53.097.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Frank McCarthy
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	LTQ Orbitrap Velos; Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2016-12-09 07:04:10	ID requested
1	2017-08-30 00:55:58	announced
⏵ 2	2024-10-22 04:39:01	announced	2024-10-22: Updated project metadata.

10.1016/j.jprot.2017.08.015;

Vyse S, McCarthy F, Broncel M, Paul A, Wong JP, Bhamra A, Huang PH, Quantitative phosphoproteomic analysis of acquired cancer drug resistance to pazopanib and dasatinib. J Proteomics, 170():130-140(2018) [pubmed]

submitter keyword: resistance, dasatinib, pazopanib,A204, phosphoproteomics

Paul Huang
contact affiliation	Protein Networks, The Institute of Cancer Research, Division of Cancer Biology, 237 Fulham Road, London, SW3 6JB, UK
contact email	paul.huang@icr.ac.uk
lab head
Frank McCarthy
contact affiliation	ICR
contact email	frank.mccarthy@icr.ac.uk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD005536
     1. Label: PRIDE project
     2. Name: Quantitative phosphoproteomic analysis of acquired drug resistance to pazopanib and dasatinib