Evidence map›Paper›PMID 34589290›Full record

ArticleOncoimmunology2021

The PKN1- TRAF1 signaling axis as a potential new target for chronic lymphocytic leukemia.

Maria I Edilova, Jaclyn C Law, Safoura Zangiabadi, Kenneth Ting, Achire N Mbanwi, Andrea Arruda, David Uehling, Methvin Isaac, Michael Prakesch, Rima Al-Awar and 3 more

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

Article in Oncoimmunology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
0.9field-weighted citation impact, top 24% 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

5 citing papers in PubMed, 9 citations in OpenAlex.

  1. Article
  2. Review
  3. Article
  4. Article
  5. Upregulation of PKN1 as a Prognosis Biomarker for Endometrial Cancer.Cancer control : journal of the Moffitt Cancer Center
    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

13 authors at 4 institutions in 2 countries.

Maria I EdilovaDepartment of Immunology, University of Toronto, Toronto, ON, Canada.
Jaclyn C LawDepartment of Immunology, University of Toronto, Toronto, ON, Canada.
Safoura ZangiabadiSchool of Kinesiology and Health Science, Muscle Health Research Centre (MHRC), Faculty of Health, York University, Toronto, ON, Canada.
Kenneth TingDepartment of Immunology, University of Toronto, Toronto, ON, Canada.
Achire N MbanwiDepartment of Immunology, University of Toronto, Toronto, ON, Canada.
Andrea ArrudaPrincess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
David UehlingDrug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
Methvin IsaacDrug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
Michael PrakeschDrug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
Rima Al-AwarDrug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
Mark D MindenPrincess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Ali A Abdul-SaterSchool of Kinesiology and Health Science, Muscle Health Research Centre (MHRC), Faculty of Health, York University, Toronto, ON, Canada.
Tania H WattsDepartment of Immunology, University of Toronto, Toronto, ON, Canada.ORCID 0000-0001-7897-4890
University of Toronto · CAOntario Institute for Cancer Research · CAUniversity Health Network · CAYork University · CA

Funding

CIHR FDN-143250
6 · The paper itself

Abstract

TRAF1 is a pro-survival adaptor molecule in TNFR superfamily (TNFRSF) signaling. TRAF1 is overexpressed in many B cell cancers including refractory chronic lymphocytic leukemia (CLL). Little has been done to assess the role of TRAF1 in human cancer. Here we show that the protein kinase C related kinase Protein Kinase N1 (PKN1) is required to protect TRAF1 from cIAP-mediated degradation during constitutive CD40 signaling in lymphoma. We show that the active phospho-Thr774 form of PKN1 is constitutively expressed in CLL but minimally detected in unstimulated healthy donor B cells. Through a screen of 700 kinase inhibitors, we identified two inhibitors, OTSSP167, and XL-228, that inhibited PKN1 in the nanomolar range and induced dose-dependent loss of TRAF1 in RAJI cells. OTSSP167 or XL-228 treatment of primary patient CLL samples led to a reduction in TRAF1, pNF-κB p65, pS6, pERK, Mcl-1 and Bcl-2 proteins, and induction of activated caspase-3. OTSSP167 synergized with venetoclax in inducing CLL death, correlating with loss of TRAF1, Mcl-1, and Bcl-2. Although correlative, these findings suggest the PKN1-TRAF1 signaling axis as a potential new target for CLL. These findings also suggest the use of the orally available inhibitor OTSSP167 in combination treatment with venetoclax for TRAF1 overexpressing CLL.

Indexed as

Leukemia, Lymphocytic, Chronic, B-CellHumansNaphthyridinesProtein Kinase CProtein Kinase InhibitorsSignal TransductionTNF Receptor-Associated Factor 11-(6-(3,5-dichloro-4-hydroxyphenyl)-4-((4-((dimethylamino)methyl)cyclohexyl)amino)-1,5-naphthyridin-3-yl)ethanoneNaphthyridinesProtein Kinase CProtein Kinase Inhibitorsprotein kinase NTNF Receptor-Associated Factor 1Chronic lymphocytic leukemiaprotein kinase N1TNFR-associated factors (TRAFS)

Identifiers

PMID34589290
PMCPMC8475556
OpenAlexW3204866712

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC
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 OpenQuestion graph.