Evidence map›Paper›PMID 34145930›Full record

ArticleCancer science2021

Trametinib overcomes KRAS-G12V-induced osimertinib resistance in a leptomeningeal carcinomatosis model of EGFR-mutant lung cancer.

Koji Fukuda, Sakiko Otani, Shinji Takeuchi, Sachiko Arai, Shigeki Nanjo, Azusa Tanimoto, Akihiro Nishiyama, Katsuhiko Naoki, Seiji Yano

Erratum issuedOpen access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cancer science, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 15 papers.

0numbers the graph read from it
0cells of the map it votes in
15citing papers in PubMed
2.8field-weighted citation impact, top 9% 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

15 citing papers in PubMed, 26 citations in OpenAlex.

  1. Targeting WEE1 to Overcome ARID1A Mutation-Driven Osimertinib Resistance in EGFR-Mutant Lung Cancer.Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer · 2025
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

9 authors at 2 institutions in 2 countries.

Koji FukudaDivision of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.ORCID https://orcid.org/0000-0001-8544-6244
Sakiko OtaniDivision of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Shinji TakeuchiDivision of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Sachiko AraiDivision of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Shigeki NanjoDivision of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Azusa TanimotoDivision of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Akihiro NishiyamaDivision of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.ORCID https://orcid.org/0000-0002-4805-9787
Katsuhiko NaokiDepartment of Respiratory Medicine, Kitasato University School of Medicine, Kanagawa, Japan.
Seiji YanoDivision of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.ORCID https://orcid.org/0000-0002-6151-2988
Kanazawa University · JPKitasato University · JP

Funding

Japan Society for the Promotion of Science 17K09649Japan Society for the Promotion of Science 18K07261Japan Society for the Promotion of Science 19H03665Japan Society for the Promotion of Science 20K17213
6 · The paper itself

Abstract

Leptomeningeal carcinomatosis (LMC) occurs frequently in non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations and is associated with acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, the mechanism by which LMC acquires resistance to osimertinib, a third-generation EGFR-TKI, is unclear. In this study, we elucidated the resistance mechanism and searched for a novel therapeutic strategy. We induced osimertinib resistance in a mouse model of LMC using an EGFR-mutant NSCLC cell line (PC9) via continuous oral osimertinib treatment and administration of established resistant cells and examined the resistance mechanism using next-generation sequencing. We detected the Kirsten rat sarcoma (KRAS)-G12V mutation in resistant cells, which retained the EGFR exon 19 deletion. Experiments involving KRAS knockdown in resistant cells and KRAS-G12V overexpression in parental cells revealed the involvement of KRAS-G12V in osimertinib resistance. Cotreatment with trametinib (a MEK inhibitor) and osimertinib resensitized the cells to osimertinib. Furthermore, in the mouse model of LMC with resistant cells, combined osimertinib and trametinib treatment successfully controlled LMC progression. These findings suggest a potential novel therapy against KRAS-G12V-harboring osimertinib-resistant LMC in EGFR-mutant NSCLC.

Indexed as

MutationAcrylamidesAniline CompoundsAnimalsAntineoplastic AgentsCarcinoma, Non-Small-Cell LungCell Line, TumorCell SurvivalCodonDrug Resistance, NeoplasmErbB ReceptorsHumansIndolesLung NeoplasmsMaleMeningeal CarcinomatosisAcrylamidesAniline CompoundsAntineoplastic AgentsCodonEGFR protein, humanErbB ReceptorsIndolesKRAS protein, humanosimertinibProtein Kinase InhibitorsProto-Oncogene Proteins p21(ras)PyridonesPyrimidinesPyrimidinonestrametinibepidermal growth factor receptorleptomeningeal carcinomatosisnon-small cell lung cancerosimertinibtrametinib

Identifiers

PMID34145930
PMCPMC8409422
OpenAlexW3172491611

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
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.