Evidence map›Paper›PMID 38438856›Full record

ArticleExperimental hematology & oncology2024

The multi-CDK inhibitor dinaciclib reverses bromo- and extra-terminal domain (BET) inhibitor resistance in acute myeloid leukemia via inhibition of Wnt/β-catenin signaling.

Alexander R Marr, Madeline Halpin, Dominique L Corbin, Yerdanos Asemelash, Steven Sher, Britten K Gordon, Ethan C Whipp, Shaneice Mitchell, Bonnie K Harrington, Shelley Orwick and 12 more

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

Article in Experimental hematology & oncology, 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
2.6field-weighted citation impact, top 11% 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

9 citing papers in PubMed, 11 citations in OpenAlex.

  1. Review
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  9. Epigenetics-targeted drugs: current paradigms and future challenges.Signal transduction and targeted therapy · 2024
    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

22 authors at 4 institutions in 1 country.

Alexander R MarrDivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Madeline HalpinDivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Dominique L CorbinDivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Yerdanos AsemelashDivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Steven SherDivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Britten K GordonDivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Ethan C WhippDivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Shaneice MitchellDepartment of Pathology, Stanford University, Stanford, CA, USA.
Bonnie K HarringtonCollege of Veterinary Medicine, Michigan State University, Lansing, MI, USA.
Shelley OrwickDivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Samon BenrashidDivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Virginia M GoettlDivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Vedat YildizDepartment of Biomedical Informatics, The Ohio State University, Columbus, OH, USA.
Andrew D MitchellDivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Olivia CahnDivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Alice S MimsDivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Karilyn T M LarkinDivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Meixao LongDivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
James BlachlyDivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Jennifer A WoyachDivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Rosa LapalombellaDivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
Nicole R GrieselhuberDivision of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA. Nicole.Grieselhuber@osumc.edu.
The Ohio State University · USThe Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute · USMichigan State University · USStanford University · US

Funding

Translational Therapeutics Research Program (TT)P30CA016058 · NCI · OHIO STATE UNIVERSITY · PI Daniel G. Stover · 1985 to 2026
$132.3M
NCI NIH HHS P30 CA016058
6 · The paper itself

Abstract

Acute myeloid leukemia (AML) is a highly aggressive hematologic cancer with poor survival across a broad range of molecular subtypes. Development of efficacious and well-tolerable therapies encompassing the range of mutations that can arise in AML remains an unmet need. The bromo- and extra-terminal domain (BET) family of proteins represents an attractive therapeutic target in AML due to their crucial roles in many cellular functions, regardless of any specific mutation. Many BET inhibitors (BETi) are currently in pre-clinical and early clinical development, but acquisition of resistance continues to remain an obstacle for the drug class. Novel methods to circumvent this development of resistance could be instrumental for the future use of BET inhibitors in AML, both as monotherapy and in combination. To date, many investigations into possible drug combinations of BETi with CDK inhibitors have focused on CDK9, which has a known physical and functional interaction with the BET protein BRD4. Therefore, we wished to investigate possible synergy and additive effects between inhibitors of these targets in AML. Here, we describe combination therapy with the multi-CDK inhibitor dinaciclib and the BETi PLX51107 in pre-clinical models of AML. Dinaciclib and PLX51107 demonstrate additive effects in AML cell lines, primary AML samples, and in vivo. Further, we demonstrate novel activity of dinaciclib through inhibition of the canonical/β-catenin dependent Wnt signaling pathway, a known resistance mechanism to BETi in AML. We show dinaciclib inhibits Wnt signaling at multiple levels, including downregulation of β-catenin, the Wnt co-receptor LRP6, as well as many Wnt pathway components and targets. Moreover, dinaciclib sensitivity remains unaffected in a setting of BET resistance, demonstrating similar inhibitory effects on Wnt signaling when compared to BET-sensitive cells. Ultimately, our results demonstrate rationale for combination CDKi and BETi in AML. In addition, our novel finding of Wnt signaling inhibition could have potential implications in other cancers where Wnt signaling is dysregulated and demonstrates one possible approach to circumvent development of BET resistance in AML.

Indexed as

AMLCombination therapyDinaciclibPLX51107ResistanceWnt signalingβ-catenin

Identifiers

PMID38438856
PMCPMC10913666
OpenAlexW4392377033

What Socratic holds

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LicenceCC BY
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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 Socratic graph.