Evidence map›Paper›PMID 25348515›Full record

ArticleClinical cancer research : an official journal of the American Association for Cancer Research2015

Low expression of the E3 ubiquitin ligase CBL confers chemoresistance in human pancreatic cancer and is targeted by epidermal growth factor receptor inhibition.

Brian E Kadera, Paul A Toste, Nanping Wu, Luyi Li, Andrew H Nguyen, David W Dawson, Timothy R Donahue

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

Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.

0numbers the graph read from it
0cells of the map it votes in
20citing papers in PubMed
1.5field-weighted citation impact, top 17% 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

20 citing papers in PubMed, 29 citations in OpenAlex.

  1. Review
  2. Review
  3. Review
  4. Ubiquitin signaling in pancreatic ductal adenocarcinoma.Frontiers in molecular biosciences · 2023
    Review
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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

7 authors at 1 institution in 1 country.

Brian E KaderaDepartment of Surgery, Division of General Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
Paul A TosteDepartment of Surgery, Division of General Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
Nanping WuDepartment of Surgery, Division of General Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
Luyi LiDepartment of Surgery, Division of General Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
Andrew H NguyenDepartment of Surgery, Division of General Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
David W DawsonDepartment of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California.
Timothy R DonahueDepartment of Surgery, Division of General Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California. tdonahue@mednet.ucla.edu.
University of California, Los Angeles · US

Funding

Pilot and Feasibility ProgramP30DK041301 · NIDDK · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ROZENGURT, JUAN ENRIQUE · 1990 to 2019
$18.0M
GASTROENTEROLOGYT32DK007180 · NIDDK · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI JENSEN, DENNIS MICHAEL · 1986 to 2025
$10.0M
Targeting diet-induced promotion of Kras-initiated pancreatic adenocarcinomaP01CA163200 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI PANDOL, STEPHEN J. · 2012 to 2016
$6.2M
PET Imaging-guided Personalized Therapy in Pancreatic CancerR01CA187678 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI CZERNIN, JOHANNES, DONAHUE, TIMOTHY R · 2014 to 2018
$2.8M
NCI NIH HHS R01 CA187678NIDDK NIH HHS P30 DK041301NIDDK NIH HHS P30 DK41301NIDDK NIH HHS T32 DK007180
6 · The paper itself

Abstract

purposeExpression of CBL, an ubiquitin ligase, is decreased in 60% of human pancreatic ductal adenocarcinomas (PDAC) and is associated with shorter overall survival. We sought to determine how low CBL directly contributes to clinically more aggressive PDAC. EXPERIMENTAL

designHuman PDACs were stained for CBL, pEGFR, and EGFR. CBL-low was modeled in PDAC cells (Panc-1, L3.6pl, and AsPC-1) via transient transfection (siRNA) or stable knockdown (shRNA). Cell viability and apoptosis were measured by MTT assays and FACS. Immunoblot and a phospho-receptor tyrosine kinase (pRTK) array were used to probe signal transduction. NOD-scid-IL2Rγ(null) mice were subcutaneously implanted with PDAC or PDAC(CBL-low) cells on opposite flanks and treated with gemcitabine ± erlotinib for ≥4 weeks.

resultsThere was an inverse correlation between CBL and pEGFR protein expression in 12 of 15 tumors. CBL knockdown increased PDAC resistance to gemcitabine and 5-fluorouracil (5-FU) by upregulating pEGFR (Y1068), pERK, and pAKT. A pRTK array of PDAC(CBL-low) cells revealed additional activated tyrosine kinases but all to a much lower magnitude than EGFR. Increased chemoresistance from low CBL was abrogated by the EGFR inhibitor erlotinib both in vitro and in vivo. Erlotinib+gemcitabine-treated PDAC(CBL-low) cells exhibited greater apoptosis by cleaved PARP, caspase-3, and Annexin V/PI.

conclusionsLow CBL causes chemoresistance in PDAC via stress-induced EGFR activation that can be effectively abrogated by EGFR inhibition. These results suggest that dysregulation of ubiquitination is a key mechanism of EGFR hyperactivation in PDAC and that low CBL may define PDAC tumors likely to respond to erlotinib treatment.

Indexed as

AdenocarcinomaAnimalsCarcinoma, Pancreatic DuctalCaspase 3Cell Line, TumorDeoxycytidineDrug Resistance, NeoplasmErbB ReceptorsErlotinib HydrochlorideGemcitabineGene Expression Regulation, NeoplasticHumansMiceProto-Oncogene Proteins c-cblQuinazolinesRNA, Small InterferingCaspase 3CBL protein, humanDeoxycytidineErbB ReceptorsErlotinib HydrochlorideGemcitabineProto-Oncogene Proteins c-cblQuinazolinesRNA, Small Interfering

Identifiers

PMID25348515
PMCPMC4286535
OpenAlexW2108247752

What OpenQuestion holds

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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.