Evidence map›Paper›PMID 42594534›Full record

ArticleGynecologic oncology2026

Feedback activation of MAPK-ERK1/2 signaling causes resistance to trastuzumab-deruxtecan in endometrial cancers.

Anh Q Nguyen, Natalia Bednarek, Ibrahim Al-Sawalha, Benedikt Nagele, Frances Moroney, Julieta B Lastra, Subin Myong, Seyyedmohsen Hosseinibarkooie, Shao Huan Samuel Weng, Katherine C Kurnit and 3 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Gynecologic oncology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
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

1 citing paper in PubMed.

  1. 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.

Anh Q NguyenDepartment of Obstetrics and Gynecology, The University of Chicago, Chicago, IL 60637, USA.
Natalia BednarekThe University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL 60637, USA.
Ibrahim Al-SawalhaThe University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL 60637, USA.
Benedikt NageleThe University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL 60637, USA.
Frances MoroneyDepartment of Obstetrics and Gynecology, The University of Chicago, Chicago, IL 60637, USA.
Julieta B LastraDepartment of Pathology, The University of Chicago, IL 60637, USA.
Subin MyongThe University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL 60637, USA.
Seyyedmohsen HosseinibarkooieProteomics Platform, The University of Chicago, IL 60637, USA.
Shao Huan Samuel WengProteomics Platform, The University of Chicago, IL 60637, USA.
Katherine C KurnitDepartment of Obstetrics and Gynecology, The University of Chicago, Chicago, IL 60637, USA.
S Diane YamadaDepartment of Obstetrics and Gynecology, The University of Chicago, Chicago, IL 60637, USA; The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL 60637, USA.
Gini F FlemingDepartment of Obstetrics and Gynecology, The University of Chicago, Chicago, IL 60637, USA; The University of Chicago Comprehensive Cancer Center, The University of Chicago, Chicago, IL 60637, USA; Department of Medicine, The University of Chicago, IL 60637, USA.
Sridevi ChallaDepartment of Obstetrics and Gynecology, The University of Chicago, Chicago, IL 60637, USA. Electronic address: challa@uchicagomedicine.org.

Funding

VIRAL ONCOLOGY CORE FACILITYP30CA014599 · NCI · UNIVERSITY OF CHICAGO · PI CHIEN-MIN KAO · 1985 to 2026
$122.1M
The Institute for Translational MedicineUL1TR002389 · NCATS · UNIVERSITY OF CHICAGO · PI Joshua J Jacobs, DAVID O MELTZER · 2017 to 2026
$71.6M
REPRODUCTIVE SCIENTIST TRAINING PROGRAMK12HD000849 · NICHD · WASHINGTON UNIVERSITY · PI Danny J Schust · 1988 to 2026
$33.2M
NCATS NIH HHS UL1 TR002389NCI NIH HHS P30 CA014599NICHD NIH HHS K12 HD000849
6 · The paper itself

Abstract

objectiveTo identify targetable pathways that can overcome resistance to trastuzumab deruxtecan (T-DXd) in endometrial cancer.

methodsWe used four endometrial cancer cell lines with different genetic backgrounds (KLE, HEC-1B, Ishikawa, and AN3 CA). Patient-derived endometrial organoids were established from surgically resected tumors and maintained in basement membrane extract with optimized media. Drug interactions were evaluated using Bliss synergy modeling. Organoid growth and treatment response were quantified by imaging-based size measurements. Protein signaling changes were analyzed by immunoblotting and comprehensive phosphoproteomic profiling. Cell cycle effects were assessed by flow cytometry. In vivo efficacy was evaluated using HEC-1B xenograft models treated with T-DXd and trametinib alone or in combination. Immunohistochemistry was performed on tumor and organoid samples to assess pathway activation and proliferation markers. Statistical analyses were conducted using GraphPad Prism 9, R and Python packages.

resultsT-DXd treatment increases ERK1/2 activation and reduces HER2 expression across various endometrial cancer cell lines. The addition of trametinib, a MEK1/2 inhibitor, to T-DXd, restores HER2 expression and markedly reduces the growth of both endometrial cancer cell lines (in vitro and in vivo), and organoids. Phosphoproteomic assays showed that T-DXd increases phosphorylation of proteins involved in DNA damage and the cell cycle, including ATR. We also found that ERK1/2 plays a key role in activating ATR and causing cell cycle arrest in the G2/M phase.

conclusionT-DXd activates ERK1/2 and ATR, which contributes to resistance, and combining T-DXd with a MEK1/2 inhibitor enhances treatment response.

Indexed as

Drug Resistance, NeoplasmEndometrial NeoplasmsMAP Kinase Signaling SystemTrastuzumabAnimalsCell Line, TumorErb-b2 Receptor Tyrosine KinasesFemaleHumansMicePyridonesPyrimidinonesXenograft Model Antitumor AssaysErb-b2 Receptor Tyrosine KinasesPyridonesPyrimidinonestrametinibTrastuzumabAntibody-drug conjugatesDrug resistanceEndometrial cancerHER2Targated therapyT-DXd

Identifiers

PMID42594534
PMCPMC13659620

What OpenQuestion holds

Textmetadata
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.