PXD008454

PXD008454 is an original dataset announced via ProteomeXchange.

Title	Adaptive resistance to Afatinib in non-small cell lung cancer cells in attenuated by Ca2+ depletion
Description	Targeted therapies against oncogenic receptor tyrosine kinases are showing promising results in the clinic. However, despite the initial response, most patients become resistant. The majority of research regarding resistance has been focused on acquired resistance occurring after an extensive time of treatment. This has resulted in the development of combination treatments. Yet, the question remains how cells are able to survive initial treatment. We hypothesize that early resistance to apoptosis will enable cells to develop any growth stimulating mechanism. Our results show that regardless of an initial drug response, drug sensitive cells rapidly adapted to targeted therapy. Within days they continued to proliferate, despite persisting target inhibition. The Non-small Cell Lung Cancer (NSCLC) PC9 cell line was used for analysis of its full proteome, kinome and phospho-proteome during early adaptive resistance development against the EGFR targeted Tyrosine Kinase Inhibitor (TKI) Afatinib. The proteomics data showed an increase in abundance and activity of cytoskeleton and calcium signaling related proteins. In addition, cells showed a distinct morphological change. We found that if cells were deprived from calcium in order to restrict them from reorganizing their cytoskeleton, they were no longer able to survive TKI treatment. This could be validated on four different NSCLC cell lines, bearing different genetic backgrounds and sensitivities to initial TKI treatment targeting the EGFR. Therapeutically, increasing the efficiency of TKI treatment, and therefore early inhibition of adaption could potentially prevent further resistance development.
HostingRepository	PRIDE
AnnounceDate	2018-10-02
AnnouncementXML	Submission_2018-10-02_04:15:36.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Celine Mulder
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2017-12-14 03:56:44	ID requested
⏵ 1	2018-10-02 04:15:37	announced

Mulder C, Prust N, van Doorn S, Reinecke M, Kuster B, van Bergen En Henegouwen P, Lemeer S, Adaptive Resistance to EGFR-Targeted Therapy by Calcium Signaling in NSCLC Cells. Mol Cancer Res, 16(11):1773-1784(2018) [pubmed]

curator keyword: Biomedical

submitter keyword: EGFR

adaptive resistance

Non-small lung Cancer

Tyrosine Kinase Inhibitors

Calcium Signaling

S.M. Lemeer
contact affiliation	Biomolecular Mass Spectrometry and Proteomics Bijvoet Center for Biomolecular Research Utrecht University
contact email	s.m.lemeer@uu.nl
lab head
Celine Mulder
contact affiliation	Utrecht University
contact email	t.c.mulder@uu.nl
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD008454
     1. Label: PRIDE project
     2. Name: Adaptive resistance to Afatinib in non-small cell lung cancer cells in attenuated by Ca2+ depletion