Evidence map›Paper›PMID 36230684›Full record

ArticleCancers2022

Phosphoproteomic Analysis Identifies TYRO3 as a Mediator of Sunitinib Resistance in Metastatic Thymomas.

Stefan Küffer, Jessica Grabowski, Satoru Okada, Nikolai Sojka, Stefan Welter, Alexander von Hammerstein-Equord, Marc Hinterthaner, Lucia Cordes, Xenia von Hahn, Denise Müller and 4 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cancers, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
0.9field-weighted citation impact, top 25% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed, 8 citations in OpenAlex.

  1. Review
  2. Article
  3. Phosphoproteomics Profile of Chicken Cecum in the Response toAnimals : an open access journal from MDPI · 2022
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors at 4 institutions in 2 countries.

Stefan KüfferInstitute of Pathology, University Medical Center Göttingen, University of Göttingen, 37075 Göttingen, Germany.ORCID 0000-0001-8443-601X
Jessica GrabowskiInstitute of Pathology, University Medical Center Göttingen, University of Göttingen, 37075 Göttingen, Germany.ORCID 0000-0002-2660-9960
Satoru OkadaInstitute of Pathology, University Medical Center Göttingen, University of Göttingen, 37075 Göttingen, Germany.ORCID 0000-0003-2627-3587
Nikolai SojkaInstitute of Pathology, University Medical Center Göttingen, University of Göttingen, 37075 Göttingen, Germany.
Stefan WelterThoracic Surgery Department, Lung Clinic Hemer, 58675 Hemer, Germany.ORCID 0000-0002-4194-8215
Alexander von Hammerstein-EquordDepartment of Thoracic and Cardiovascular Surgery, University Medical Center, 37075 Göttingen, Germany.
Marc HinterthanerDepartment of Thoracic and Cardiovascular Surgery, University Medical Center, 37075 Göttingen, Germany.
Lucia CordesThoracic Surgery Department, Lung Clinic Hemer, 58675 Hemer, Germany.
Xenia von HahnInstitute of Pathology, University Medical Center Göttingen, University of Göttingen, 37075 Göttingen, Germany.ORCID 0000-0002-5301-7493
Denise MüllerInstitute of Pathology, University Medical Center Göttingen, University of Göttingen, 37075 Göttingen, Germany.ORCID 0000-0001-6231-7431
Christian SauerInstitute of Pathology, University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
Hanibal BohnenbergerInstitute of Pathology, University Medical Center Göttingen, University of Göttingen, 37075 Göttingen, Germany.ORCID 0000-0003-1038-1030
Alexander MarxInstitute of Pathology, University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany.ORCID 0000-0001-9722-2483
Philipp StröbelInstitute of Pathology, University Medical Center Göttingen, University of Göttingen, 37075 Göttingen, Germany.ORCID 0000-0002-8528-8060
Universitätsmedizin Göttingen · DEHeidelberg University · DELungenklinik Hemer · DEKyoto Prefectural University of Medicine · JP

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundAfter initially responding to empiric radio-chemotherapy, most advanced thymomas (TH) and thymic carcinomas (TC) become refractory and require second-line therapy. The multi-target receptor tyrosine kinase (RTK) inhibitor, sunitinib, is one of the few options, especially in patients with thymic carcinomas, and has resulted in partial remissions and prolonged overall survival. However, sunitinib shows variable activity in thymomas, and not all patients benefit equally. A better understanding of its mode of action and the definition of predictive biomarkers would help select patients who profit most.

methodsSix cell lines were treated with sunitinib in vitro. Cell viability was measured by MTS assay and used to define in vitro responders and non-responders. A quantitative real-time assay simultaneously measuring the phosphorylation of 144 tyrosine kinase substrates was used to correlate cell viability with alterations of the phospho-kinome, calculate a sunitinib response index (SRI), and impute upstream tyrosine kinases. Sunitinib was added to protein lysates of 29 malignant TH and TC. Lysates were analyzed with the same phosphorylation assay. The SRI tentatively classified cases into potential clinical responders and non-responders. In addition, the activation patterns of 44 RTKs were studied by phospho-RTK arrays in 37 TH and TC.

resultsSRI application separated thymic epithelial tumors (TET) in potential sunitinib responders and resistant cases. Upstream kinase prediction identified multiple RTKs potentially involved in sunitinib response, many of which were subsequently shown to be differentially overexpressed in TH and TC. Among these, TYRO3/Dtk stood out since it was exclusively present in metastatic TH. The function of TYRO3 as a mediator of sunitinib resistance was experimentally validated in vitro.

conclusionsUsing indirect and direct phosphoproteomic analyses to predict sunitinib response in malignant TET, we have shown that TH and TC express multiple important sunitinib target RTKs. Among these, TYRO3 was identified as a potent mediator of sunitinib resistance activity, specifically in metastatic TH. TYRO3 may thus be both a novel biomarker of sunitinib resistance and a potential therapeutic target in advanced thymomas and thymic carcinomas.

Indexed as

biomarkerdrug responsephosphoproteomicssunitinibthymic carcinomathymomaTYRO3tyrosine kinase

Identifiers

PMID36230684
PMCPMC9562918
OpenAlexW4297973738

What Socratic holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.