Evidence map›Paper›PMID 40500731›Full record

ArticleMolecular medicine (Cambridge, Mass.)2025

ONECUT2 reprograms neuroendocrine fate and is an actionable therapeutic target in small cell lung cancer.

Mirian Gutiérrez, Irene Zamora, Raquel Iriarte, María José Pajares, Qian Yang, Chen Qian, Nerea Otegui, Joaquín Fernández-Irigoyen, Enrique Santamaría, Nicolas Alcala and 10 more

Abstract read
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In one paragraph

Article in Molecular medicine (Cambridge, Mass.), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing 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

0 citing papers in PubMed.

No citing paper in PubMed yet.

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

20 authors.

Mirian Gutiérrez *Department of Health Sciences, Public University of Navarre, Pamplona, Navarre, Spain.
Irene Zamora *Department of Health Sciences, Public University of Navarre, Pamplona, Navarre, Spain.
Raquel IriarteDepartment of Health Sciences, Public University of Navarre, Pamplona, Navarre, Spain.
María José PajaresDepartment of Health Sciences, Public University of Navarre, Pamplona, Navarre, Spain.
Qian YangDepartment of Urology and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Chen QianDepartment of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Nerea OteguiCenter for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarre, Spain.
Joaquín Fernández-IrigoyenDepartment of Health Sciences, Public University of Navarre, Pamplona, Navarre, Spain.
Enrique SantamaríaDepartment of Health Sciences, Public University of Navarre, Pamplona, Navarre, Spain.
Nicolas AlcalaRare Cancers Genomics Team (RCG), Genomic Epidemiology Branch (GEM), International Agency for Research On Cancer/World Health Organization (IARC/WHO), Lyon, France.
Alexandra Sexton-OatesRare Cancers Genomics Team (RCG), Genomic Epidemiology Branch (GEM), International Agency for Research On Cancer/World Health Organization (IARC/WHO), Lyon, France.
Lynnette Fernández-CuestaRare Cancers Genomics Team (RCG), Genomic Epidemiology Branch (GEM), International Agency for Research On Cancer/World Health Organization (IARC/WHO), Lyon, France.
Miguel BarajasDepartment of Health Sciences, Public University of Navarre, Pamplona, Navarre, Spain.
Alfonso CalvoCenter for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarre, Spain.
Luis M MontuengaCenter for Applied Medical Research (CIMA), University of Navarra, Pamplona, Navarre, Spain.
Beatrice KnudsenDepartment of Pathology, University of Utah, Salt Lake City, UT, USA.
Sungyong YouDepartment of Urology and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Michael R FreemanDepartment of Urology and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Ignacio EncíoDepartment of Health Sciences, Public University of Navarre, Pamplona, Navarre, Spain.
Mirja RotinenDepartment of Health Sciences, Public University of Navarre, Pamplona, Navarre, Spain. mirja.rotinen@unavarra.es.

Funding

World Health Organization 001
6 · The paper itself

Abstract

Small cell lung cancer (SCLC) is a highly aggressive malignancy with extremely poor prognosis. SCLC cells exhibit high plasticity and can progress from neuroendocrine (NE) to non-NE phenotypes. This dynamic evolution promotes treatment resistance and relapses, representing a challenge for targeted therapies in this elusive disease. Here we identify the transcription factor ONECUT2 (OC2) as a driver of plasticity in SCLC, leading to non-NE transcriptional states. OC2 is highly expressed in SCLC tumors compared to normal lung tissue and its expression is associated with heightened clinical stage and lymph node metastasis. We show that OC2 is a repressor of ASCL1, the NE master regulator transcription factor. In addition, OC2 upregulates non-NE programs through activation of c-MYC and Notch signaling. We also demonstrate that OC2 is required for growth and survival of SCLC cells and that it can be targeted with a small molecule inhibitor that acts synergistically with the standard combination of cisplatin and etoposide, providing a novel therapeutic strategy for OC2 active SCLC tumors.

Indexed as

Lung NeoplasmsSmall Cell Lung CarcinomaTranscription FactorsAnimalsBasic Helix-Loop-Helix ProteinsCell Line, TumorCisplatinEtoposideGene Expression Regulation, NeoplasticHumansMiceNeuroendocrine CellsReceptors, NotchSignal TransductionASCL1 protein, humanBasic Helix-Loop-Helix ProteinsCisplatinEtoposideReceptors, NotchTranscription FactorsONECUT2Phenotypic plasticitySCLCTherapeutic targetTumor heterogeneity

Identifiers

PMID40500731
PMCPMC12153148

What OpenQuestion holds

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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 OpenQuestion graph.