Evidence map›Paper›PMID 36175617›Full record

ArticleBritish journal of cancer2022

Concurrent inhibition of CDK2 adds to the anti-tumour activity of CDK4/6 inhibition in GIST.

Inga-Marie Schaefer, Matthew L Hemming, Meijun Z Lundberg, Matthew P Serrata, Isabel Goldaracena, Ninning Liu, Peng Yin, Joao A Paulo, Steven P Gygi, Suzanne George and 12 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in British journal of cancer, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.

0numbers the graph read from it
0cells of the map it votes in
20citing papers in PubMed
4.0field-weighted citation impact, top 5% 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

20 citing papers in PubMed, 25 citations in OpenAlex.

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  13. Targeting CDK2 to combat drug resistance in cancer therapy.Future oncology (London, England) · 2024
    Review
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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

22 authors at 3 institutions in 3 countries.

Inga-Marie SchaeferDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. ischaefer@bwh.harvard.edu.ORCID http://orcid.org/0000-0001-9710-5500
Matthew L HemmingDepartment of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0003-4674-7778
Meijun Z LundbergDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Matthew P SerrataWyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.
Isabel GoldaracenaWyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.
Ninning LiuWyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.
Peng YinWyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.
Joao A PauloDepartment of Cell Biology, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-4291-413X
Steven P GygiDepartment of Cell Biology, Harvard Medical School, Boston, MA, USA.
Suzanne GeorgeDepartment of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Jeffrey A MorganDepartment of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Monica M BertagnolliDepartment of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Ewa T SicinskaDepartment of Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Chen ChuDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Shanshan ZhengDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
Adrian Mariño-EnríquezDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-7680-9901
Jason L HornickDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0001-6475-8345
Chandrajit P RautSarcoma Center, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA, USA.
Wen-Bin OuDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0002-6311-9442
George D DemetriDepartment of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Sinem K SakaWyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.ORCID http://orcid.org/0000-0002-5017-379X
Jonathan A FletcherDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Brigham and Women's Hospital · USHarvard University · USEuropean Molecular Biology Laboratory · DE

Funding

High-throughput single-molecule protein identification via super-resolution imagingDP1GM133052 · NIGMS · HARVARD UNIVERSITY · PI YIN, PENG · 2018 to 2022
$6.6M
Advancing Multiplexed Isobaric Tag-based Strategies for Proteome ProfilingR01GM132129 · NIGMS · HARVARD MEDICAL SCHOOL · PI PAULO, JOAO A · 2019 to 2023
$1.7M
Targeting cell cycle dysregulation in GISTK08CA241085 · NCI · BRIGHAM AND WOMEN'S HOSPITAL · PI SCHAEFER, INGA-MARIE · 2019 to 2023
$1.5M
Defining clinically relevant transcriptional networks in gastrointestinal stromal tumorK08CA245235 · NCI · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI HEMMING, MATTHEW · 2020 to 2024
$1.2M
NCI NIH HHS K08 CA241085NCI NIH HHS K08 CA245235NIGMS NIH HHS DP1 GM133052NIGMS NIH HHS R01 GM132129
6 · The paper itself

Abstract

backgroundAdvanced gastrointestinal stromal tumour (GIST) is characterised by genomic perturbations of key cell cycle regulators. Oncogenic activation of CDK4/6 results in RB1 inactivation and cell cycle progression. Given that single-agent CDK4/6 inhibitor therapy failed to show clinical activity in advanced GIST, we evaluated strategies for maximising response to therapeutic CDK4/6 inhibition.

methodsTargeted next-generation sequencing and multiplexed protein imaging were used to detect cell cycle regulator aberrations in GIST clinical samples. The impact of inhibitors of CDK2, CDK4 and CDK2/4/6 was determined through cell proliferation and protein detection assays. CDK-inhibitor resistance mechanisms were characterised in GIST cell lines after long-term exposure.

resultsWe identify recurrent genomic aberrations in cell cycle regulators causing co-activation of the CDK2 and CDK4/6 pathways in clinical GIST samples. Therapeutic co-targeting of CDK2 and CDK4/6 is synergistic in GIST cell lines with intact RB1, through inhibition of RB1 hyperphosphorylation and cell proliferation. Moreover, RB1 inactivation and a novel oncogenic cyclin D1 resulting from an intragenic rearrangement (CCND1::chr11.g:70025223) are mechanisms of acquired CDK-inhibitor resistance in GIST.

conclusionsThese studies establish the biological rationale for CDK2 and CDK4/6 co-inhibition as a therapeutic strategy in patients with advanced GIST, including metastatic GIST progressing on tyrosine kinase inhibitors.

Indexed as

Gastrointestinal NeoplasmsGastrointestinal Stromal TumorsCyclin-Dependent Kinase 2Cyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6HumansCDK2 protein, humanCDK4 protein, humanCyclin-Dependent Kinase 2Cyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6

Identifiers

PMID36175617
PMCPMC9681737
OpenAlexW4298005294

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.