Evidence map›Paper›PMID 39120974›Full record

ArticleCell reports2024

GCN2 is a determinant of the response to WEE1 kinase inhibition in small-cell lung cancer.

Alexandros P Drainas, Wen-Hao Hsu, Alec E Dallas, Carson D Poltorack, Jun W Kim, Andy He, Garry L Coles, Maya Baron, Michael C Bassik, Julien Sage

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell reports, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.

0numbers the graph read from it
0cells of the map it votes in
9citing 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

9 citing papers in PubMed.

  1. Article
  2. Article
  3. Review
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  5. Article
  6. Review
  7. Article
  8. Article
  9. BRAFbioRxiv : the preprint server for biology · 2024
    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

10 authors.

Alexandros P DrainasDepartment of Pediatrics, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA.
Wen-Hao HsuDepartment of Pediatrics, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA.
Alec E DallasDepartment of Pediatrics, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA.
Carson D PoltorackDepartment of Pediatrics, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA.
Jun W KimDepartment of Pediatrics, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA.
Andy HeDepartment of Pediatrics, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA.
Garry L ColesDepartment of Pediatrics, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA.
Maya BaronDepartment of Pediatrics, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA.
Michael C BassikDepartment of Genetics, Stanford University, Stanford, CA, USA.
Julien SageDepartment of Pediatrics, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA. Electronic address: julsage@stanford.edu.

Funding

Novel therapeutic approaches for enhancing anti-tumor immunity in SCLCU01CA213273 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI BYERS, LAUREN AVERETT, HEYMACH, JOHN V. · 2017 to 2021
$3.0M
Oncogenic Kras drives stromal adipogenesis to promote colorectal cancer (CRC) progressionK00CA274661 · NCI · STANFORD UNIVERSITY · PI Wen-Hao Hsu · 2024 to 2026
$297k
NCI NIH HHS K00 CA274661NCI NIH HHS U01 CA213273
6 · The paper itself

Abstract

Patients with small-cell lung cancer (SCLC) are in dire need of more effective therapeutic options. Frequent disruption of the G1 checkpoint in SCLC cells creates a dependency on the G2/M checkpoint to maintain genomic integrity. Indeed, in pre-clinical models, inhibiting the G2/M checkpoint kinase WEE1 shows promise in inhibiting SCLC growth. However, toxicity and acquired resistance limit the clinical effectiveness of this strategy. Here, using CRISPR-Cas9 knockout screens in vitro and in vivo, we identified multiple factors influencing the response of SCLC cells to the WEE1 kinase inhibitor AZD1775, including the GCN2 kinase and other members of its signaling pathway. Rapid activation of GCN2 upon AZD1775 treatment triggers a stress response in SCLC cells. Pharmacological or genetic activation of the GCN2 pathway enhances cancer cell killing by AZD1775. Thus, activation of the GCN2 pathway represents a promising strategy to increase the efficacy of WEE1 inhibitors in SCLC.

Indexed as

Cell Cycle ProteinsLung NeoplasmsProtein Kinase InhibitorsProtein Serine-Threonine KinasesProtein-Tyrosine KinasesPyrimidinonesSmall Cell Lung CarcinomaAnimalsCell Line, TumorHumansMiceMice, NudePyrazolesSignal TransductionadavosertibCell Cycle ProteinsEIF2AK4 protein, humanProtein Kinase InhibitorsProtein Serine-Threonine KinasesProtein-Tyrosine KinasesPyrazolesPyrimidinonesWEE1 protein, humanAZD1775CP: CancerCRISPR-Cas9drug resistanceGCN2ISRPP1Raphin1SCLCWEE1

Identifiers

PMID39120974
PMCPMC11407228

What OpenQuestion holds

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Registered trials

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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.