Evidence map›Paper›PMID 40518016›Full record

ArticleJournal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer2025

Targeting WEE1 to Overcome ARID1A Mutation-Driven Osimertinib Resistance in EGFR-Mutant Lung Cancer.

Koji Fukuda, Shigeki Nanjo, Shinji Takeuchi, Turja Chakrabarti, Tyiesha Brown, Sharon Wesley Dev Sahadevan, Sachiko Arai, Shigeki Sato, Hiroshi Kotani, Akihiro Nishiyama and 6 more

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Article in Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.

0numbers the graph read from it
0cells of the map it votes in
4citing 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

4 citing papers in PubMed.

  1. Review
  2. Article
  3. Article
  4. Review
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

16 authors.

Koji FukudaDivision of Innovative Cancer Control Research, Cancer Research Institute, Kanazawa University, Kanazawa, Japan; Nano Life Science Institute, Kanazawa University, Kanazawa, Japan. Electronic address: kfukuda@staff.kanazawa-u.ac.jp.
Shigeki NanjoDepartment of Respiratory Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kanazawa, Japan.
Shinji TakeuchiDivision of Innovative Cancer Control Research, Cancer Research Institute, Kanazawa University, Kanazawa, Japan; Nano Life Science Institute, Kanazawa University, Kanazawa, Japan; Department of Medical Oncology, Kanazawa University Hospital, Kanazawa, Japan.
Turja ChakrabartiDepartment of Medicine, University of California, San Francisco, California.
Tyiesha BrownDepartment of Medicine, University of California, San Francisco, California.
Sharon Wesley Dev SahadevanDepartment of Medicine, University of California, San Francisco, California.
Sachiko AraiNano Life Science Institute, Kanazawa University, Kanazawa, Japan.
Shigeki SatoDivision of Innovative Cancer Control Research, Cancer Research Institute, Kanazawa University, Kanazawa, Japan; Department of Medical Oncology, Kanazawa University Hospital, Kanazawa, Japan.
Hiroshi KotaniDivision of Innovative Cancer Control Research, Cancer Research Institute, Kanazawa University, Kanazawa, Japan; Department of Medical Oncology, Kanazawa University Hospital, Kanazawa, Japan.
Akihiro NishiyamaDivision of Innovative Cancer Control Research, Cancer Research Institute, Kanazawa University, Kanazawa, Japan; Department of Medical Oncology, Kanazawa University Hospital, Kanazawa, Japan.
Hiroyuki SakaguchiDivision of Innovative Cancer Control Research, Cancer Research Institute, Kanazawa University, Kanazawa, Japan; Department of Medical Oncology, Kanazawa University Hospital, Kanazawa, Japan.
Koushiro OhtsuboDivision of Innovative Cancer Control Research, Cancer Research Institute, Kanazawa University, Kanazawa, Japan; Department of Medical Oncology, Kanazawa University Hospital, Kanazawa, Japan.
Hiroaki TaniguchiDivision of Innovative Cancer Control Research, Cancer Research Institute, Kanazawa University, Kanazawa, Japan; Department of Medical Oncology, Kanazawa University Hospital, Kanazawa, Japan.
Collin M BlakelyDepartment of Medicine, University of California, San Francisco, California.
Trever G BivonaDepartment of Medicine, University of California, San Francisco, California; Chan-Zuckerberg, Biohub, San Francisco, California.
Seiji YanoNano Life Science Institute, Kanazawa University, Kanazawa, Japan; Department of Respiratory Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kanazawa, Japan.

Funding

UCSF Project 1U54CA224081 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CALVIN J KUO · 2017 to 2026
$12.9M
Bay Area Cancer Target Discovery and DevelopmentU01CA272546 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Sourav Bandyopadhyay, Trever G Bivona · 2022 to 2026
$4.8M
Dissecting the role and mechanism of EML4-ALK condensates in oncogenic signaling and tumor growthR01CA279180 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Trever G Bivona, Bo Huang · 2023 to 2026
$2.6M
NCI NIH HHS R01 CA279180NCI NIH HHS U01 CA272546NCI NIH HHS U54 CA224081
6 · The paper itself

Abstract

introductionOsimertinib, a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI), is commonly used as a first-line treatment for EGFR-mutant NSCLC. Nevertheless, despite its efficacy, resistance remains a major clinical challenge with unknown underlying mechanisms. This study aimed to investigate the mechanisms driving osimertinib resistance and identify therapeutic strategies.

methodsUsing a mouse model of leptomeningeal carcinomatosis, we induced osimertinib resistance and performed next-generation sequencing to characterize resistance-associated mutations. We also analyzed clinical samples to correlate ARID1A status with progression-free survival and overall survival in patients receiving osimertinib.

resultsMutations in the AT-rich interacting domain-containing protein 1A (ARID1A) gene were the most prevalent in resistant cells. Functional assays revealed that ARID1A knockout in parental cells and wild-type ARID1A gene expression in resistant cells were critical in conferring osimertinib resistance. A Clustered Regularly Interspaced Short Palindromic Repeats-Cas9 knockout screen identified WEE1 kinase as a potent enhancer of apoptosis in ARID1A-mutant osimertinib-resistant cells. Mechanistically, ARID1A-mutant cells exhibited reduced expression of genes involved in cell cycle regulation and DNA repair, rendering them particularly sensitive to WEE1 inhibition. In the leptomeningeal carcinomatosis mouse model, the combined inhibition of EGFR and WEE1 significantly suppressed tumor growth. Clinically, patients with ARID1A mutations treated with osimertinib had significantly shorter median progression-free survival (6.25 versus 18.0 months, p = 0.0036) and overall survival (17.0 versus 34.0 months, p = 0.024) than did those with wild-type ARID1A.

conclusionsThese findings suggest that ARID1A mutations are critical biomarkers for osimertinib resistance and highlight WEE1 inhibition as a promising therapeutic approach for ARID1A-mutant osimertinib-resistant NSCLC.

Indexed as

AcrylamidesAniline CompoundsCarcinoma, Non-Small-Cell LungCell Cycle ProteinsDNA-Binding ProteinsDrug Resistance, NeoplasmLung NeoplasmsProtein-Tyrosine KinasesTranscription FactorsAnimalsErbB ReceptorsFemaleHumansIndolesMaleMiceAcrylamidesAniline CompoundsARID1A protein, humanCell Cycle ProteinsDNA-Binding ProteinsEGFR protein, humanErbB ReceptorsIndolesosimertinibProtein Kinase InhibitorsProtein-Tyrosine KinasesPyrimidinesTranscription FactorsWEE1 protein, humanARID1A mutationDrug resistanceLeptomeningeal carcinomatosisOsimertinibWEE1 kinase

Identifiers

PMID40518016
PMCPMC13310150

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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.