Evidence map›Paper›PMID 35839938›Full record

ArticleRadiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology2022

Targeting HER3-dependent activation of nuclear AKT improves radiotherapy of non-small cell lung cancer.

Mahmoud Toulany, Mari Iida, Konstanze Lettau, John P Coan, Simone Rebholz, Shayan Khozooei, Paul M Harari, Deric L Wheeler

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

Article in Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
0.6field-weighted citation impact, top 36% 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

7 citing papers in PubMed, 8 citations in OpenAlex.

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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

8 authors at 3 institutions in 2 countries.

Mahmoud ToulanyDivision of Radiobiology and Molecular Environmental Research, Department of Radation Oncology, University of Tuebingen, Tuebingen, Germany; German Cancer Consortium (DKTK), Partner Site Tuebingen, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: mahmoud.toulany@uni-tuebingen.de.
Mari IidaDepartment of Human Oncology, University of Wisconsin, Madison, WI, USA.
Konstanze LettauDivision of Radiobiology and Molecular Environmental Research, Department of Radation Oncology, University of Tuebingen, Tuebingen, Germany.
John P CoanDepartment of Human Oncology, University of Wisconsin, Madison, WI, USA.
Simone RebholzDivision of Radiobiology and Molecular Environmental Research, Department of Radation Oncology, University of Tuebingen, Tuebingen, Germany.
Shayan KhozooeiDivision of Radiobiology and Molecular Environmental Research, Department of Radation Oncology, University of Tuebingen, Tuebingen, Germany.
Paul M HarariDepartment of Human Oncology, University of Wisconsin, Madison, WI, USA.
Deric L WheelerDepartment of Human Oncology, University of Wisconsin, Madison, WI, USA.
University of Wisconsin–Madison · USUniversity of Tübingen · DEGerman Cancer Research Center · DE

Funding

UW COMPREHENSIVE CANCER CENTER SUPPORTP30CA014520 · NCI · UNIVERSITY OF WISCONSIN-MADISON · PI Christian Capitini · 1985 to 2026
$142.6M
Automated Tissue MicroarrayerS10OD023526 · OD · UNIVERSITY OF WISCONSIN-MADISON · PI MATKOWSKYJ, KRISTINA A. · 2018 to 2018
$184k
NCI NIH HHS P30 CA014520NIH HHS S10 OD023526
6 · The paper itself

Abstract

backgroundAKT1 must be present and activated in the nucleus immediately after irradiation to stimulate AKT1-dependent double-strand breaks (DSB) repair through the fast non-homologous end-joining (NHEJ) repair process. We investigated the subcellular distribution of AKT1 and the role of HER family receptor members on the phosphorylation of nuclear AKT and radiation response. MATERIALS AND

methodsUsing genetic approaches and pharmacological inhibitors, we investigated the subcellular distribution of AKT1 and the role of HER family receptor members on the activation of nuclear AKT in non-small cell lung cancer (NSCLC) cells in vitro. ɤH2AX foci assay was applied to investigate the role of AKT activating signaling pathway on DSB repair. A mouse tumor xenograft model was used to study the impact of discovered signaling pathway activating nuclear AKT on the radiation response of tumors in vivo.

resultsOur data suggests that neither ionizing radiation (IR) nor stimulation with HER family receptor ligands induced rapid nuclear translocation of endogenous AKT1. GFP-tagged exogenous AKT1 translocated to the nucleus under un-irradiated conditions and IR did not stimulate this translocation. Nuclear translocation of GFP-AKT1 was impaired by the AKT inhibitor MK2206 as shown by its accumulation in the cytoplasmic fraction. IR-induced phosphorylation of nuclear AKT was primarily dependent on HER3 expression and tyrosine kinase activation of epidermal growth factor receptor. In line with the role of AKT1 in DSB repair, the HER3 neutralizing antibody patritumab as well as HER3-siRNA diminished DSB repair in vitro. Combination of patritumab with radiotherapy improved the effect of radiotherapy on tumor growth delay in a xenograft model.

conclusionIR-induced activation of nuclear AKT occurs inside the nucleus that is mainly dependent on HER3 expression in NSCLC. These findings suggest that targeting HER3 in combination with radiotherapy may provide a logical treatment option for investigation in selected NSCLC patients.

Indexed as

Carcinoma, Non-Small-Cell LungLung NeoplasmsAnimalsAntibodies, NeutralizingCell Line, TumorDNA Breaks, Double-StrandedDNA RepairErbB ReceptorsHumansMiceProto-Oncogene Proteins c-aktRNA, Small InterferingAntibodies, NeutralizingErbB ReceptorsProto-Oncogene Proteins c-aktRNA, Small InterferingDNA repairHER3Non-small cell lung cancerNuclear AKTRadioresistance

Identifiers

PMID35839938
PMCPMC10083767
OpenAlexW4285498963

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.