Evidence map›Paper›PMID 25882699›Full record

ArticleLeukemia2015

Synergistic induction of apoptosis in high-risk DLBCL by BCL2 inhibition with ABT-199 combined with pharmacologic loss of MCL1.

L Li, P Pongtornpipat, T Tiutan, S L Kendrick, S Park, D O Persky, L M Rimsza, S D Puvvada, J H Schatz

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

Article in Leukemia, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 63 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
63citing papers in PubMed, 2 pooled it
10.0field-weighted citation impact, top 1% 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

63 citing papers in PubMed, 2 syntheses or guidelines pooled it, 95 citations in OpenAlex.

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3 more citing papers are in PubMed but not listed here.

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

9 authors at 2 institutions in 1 country.

L LiBio5 Institute, University of Arizona Cancer Center, Tucson, AZ, USA.
P PongtornpipatBio5 Institute, University of Arizona Cancer Center, Tucson, AZ, USA.
T TiutanCollege of Medicine, University of Arizona Cancer Center, Tucson, AZ, USA.
S L KendrickDepartment of Pathology, University of Arizona Cancer Center, Tucson, AZ, USA.
S ParkDepartment of Medicine, University of Arizona Cancer Center, Tucson, AZ, USA.
D O PerskyDepartment of Medicine, University of Arizona Cancer Center, Tucson, AZ, USA.
L M RimszaDepartment of Pathology, University of Arizona Cancer Center, Tucson, AZ, USA.
S D PuvvadaDepartment of Medicine, University of Arizona Cancer Center, Tucson, AZ, USA.
J H Schatz1] Bio5 Institute, University of Arizona Cancer Center, Tucson, AZ, USA [2] Department of Medicine, University of Arizona Cancer Center, Tucson, AZ, USA [3] Department of Pharmacology and Toxicology, University of Arizona Cancer Center, Tucson, AZ, USA.
University of Arizona · USUniversity of Arizona Cancer Center

Funding

VITAMIN AP30CA023074 · NCI · UNIVERSITY OF ARIZONA · PI Dan Theodorescu · 1985 to 2026
$110.2M
Summer Translational Oncology Program (STOP)R25CA171973 · NCI · JOHNS HOPKINS UNIVERSITY · PI BUNZ, FRED, EMENS, LEISHA A · 2013 to 2017
$340k
NCI NIH HHS P30 CA023074NCI NIH HHS P30CA023074-34NCI NIH HHS R25 CA171973
6 · The paper itself

Abstract

Better treatments are needed for patients with diffuse large B-cell lymphoma (DLBCL) at high risk of failing standard therapy. Avoiding apoptosis is a hallmark of cancer, and in DLBCL the redundantly functioning antiapoptotic proteins BCL2 and MCL1 are frequently expressed. Here we explore drugs that cause loss of MCL1, particularly the potent new cyclin-dependent kinase inhibitor dinaciclib, which knocks down MCL1 by inhibiting CDK9. Dinaciclib induces apoptosis in DLBCL cells but is completely overcome by increased activity of BCL2. We find that clinical samples have frequent co-expression of MCL1 and BCL2, suggesting that therapeutic strategies targeting only one will lead to treatment failures owing to activity of the other. The BH3 mimetic ABT-199 potently and specifically targets BCL2. Single-agent ABT-199 had modest antitumor activity against most DLBCL lines and resulted in compensatory upregulation of MCL1 expression. ABT-199 synergized strongly, however, when combined with dinaciclib and with other drugs affecting MCL1, including standard DLBCL chemotherapy drugs. We show potent antitumor activities of these combinations in xenografts and in a genetically accurate murine model of MYC-BCL2 double-hit lymphoma. In sum, we reveal a rational treatment paradigm to strip DLBCL of its protection from apoptosis and improve outcomes for high-risk patients.

Indexed as

Drug SynergismAnimalsAntineoplastic Combined Chemotherapy ProtocolsApoptosisBridged Bicyclo Compounds, HeterocyclicCell ProliferationCyclic N-OxidesFemaleHumansImmunoenzyme TechniquesIndolizinesLymphoma, Large B-Cell, DiffuseMiceMice, Inbred NODMice, SCIDMyeloid Cell Leukemia Sequence 1 ProteinBridged Bicyclo Compounds, HeterocyclicCyclic N-OxidesdinaciclibIndolizinesMCL1 protein, humanMyeloid Cell Leukemia Sequence 1 ProteinProto-Oncogene Proteins c-bcl-2Pyridinium CompoundsRNA, MessengerSulfonamidesvenetoclax

Identifiers

PMID25882699
PMCPMC4526343
OpenAlexW2083470652

What OpenQuestion holds

Textmetadata
LicenceTDM
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.