Evidence map›Paper›PMID 31123034›Full record

ArticleHaematologica2020

Concomitant targeting of BCL2 with venetoclax and MAPK signaling with cobimetinib in acute myeloid leukemia models.

Lina Han, Qi Zhang, Monique Dail, Ce Shi, Antonio Cavazos, Vivian R Ruvolo, Yang Zhao, Eugene Kim, Mohamed Rahmani, Duncan H Mak and 16 more

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

Article in Haematologica, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
74citing papers in PubMed, 2 pooled it
11.5field-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

74 citing papers in PubMed, 2 syntheses or guidelines pooled it, 113 citations in OpenAlex.

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  18. Targeting CCL2/CCR2 Signaling Overcomes MEK Inhibitor Resistance in Acute Myeloid Leukemia.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024
    Article
  19. Review
  20. Article

14 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

26 authors at 4 institutions in 3 countries.

Lina HanDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Qi ZhangDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Monique DailDepartment of Oncology Biomarkers, Genentech, South San Francisco, CA, USA.
Ce ShiDepartment of Hematology, First Affiliated Hospital, Harbin Medical University, Harbin, China.
Antonio CavazosDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Vivian R RuvoloDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Yang ZhaoDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Eugene KimDepartment of Oncology Biomarkers, Genentech, South San Francisco, CA, USA.
Mohamed RahmaniCollege of Medicine, Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE.
Duncan H MakDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Sha S JinAbbVie Inc., North Chicago, IL, USA.
Jun ChenAbbVie Inc., North Chicago, IL, USA.
Darren C PhillipsAbbVie Inc., North Chicago, IL, USA.
Paul Bottecelli KollerDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Rodrigo JacamoDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jared K BurksDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Courtney DiNardoDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Naval DaverDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Elias JabbourDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jing WangDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Hagop M KantarjianDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Michael AndreeffDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Steven GrantDivision of Hematology/Oncology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA.
Joel D LeversonAbbVie Inc., North Chicago, IL, USA.
Deepak SampathDepartment of Translational Oncology, Genentech, South San Francisco, CA, USA.
Marina KonoplevaDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA mkonople@mdanderson.org.
The University of Texas MD Anderson Cancer Center · USAbbVie (United States) · USHarbin Medical University · CNVirginia Commonwealth University · US

Funding

Tumor Evolution and Metastasis ProgramP30CA016672 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Scott Kopetz · 1985 to 2026
$290.8M
Targeting Multiple Myeloma with Smac-mimetics and HDAC InhibitorsR01CA205607 · NCI · VIRGINIA COMMONWEALTH UNIVERSITY · PI GRANT, STEVEN · 2016 to 2020
$1.6M
NCI NIH HHS P30 CA016672NCI NIH HHS R01 CA205607
6 · The paper itself

Abstract

The pathogenesis of acute myeloid leukemia (AML) involves serial acquisition of mutations controlling several cellular processes, requiring combination therapies affecting key downstream survival nodes in order to treat the disease effectively. The BCL2 selective inhibitor venetoclax has potent anti-leukemia efficacy; however, resistance can occur due to its inability to inhibit MCL1, which is stabilized by the MAPK pathway. In this study, we aimed to determine the anti-leukemia efficacy of concomitant targeting of the BCL2 and MAPK pathways by venetoclax and the MEK1/2 inhibitor cobimetinib, respectively. The combination demonstrated synergy in seven of 11 AML cell lines, including those resistant to single agents, and showed growth-inhibitory activity in over 60% of primary samples from patients with diverse genetic alterations. The combination markedly impaired leukemia progenitor functions, while maintaining normal progenitors. Mass cytometry data revealed that BCL2 protein is enriched in leukemia stem/progenitor cells, primarily in venetoclax-sensitive samples, and that cobimetinib suppressed cytokine-induced pERK and pS6 signaling pathways. Through proteomic profiling studies, we identified several pathways inhibited downstream of MAPK that contribute to the synergy of the combination. In OCI-AML3 cells, the combination downregulated MCL1 protein levels and disrupted both BCL2:BIM and MCL1:BIM complexes, releasing BIM to induce cell death. RNA sequencing identified several enriched pathways, including MYC, mTORC1, and p53 in cells sensitive to the drug combination.

Indexed as

Leukemia, Myeloid, AcuteProteomicsApoptosisAzetidinesBridged Bicyclo Compounds, HeterocyclicCell Line, TumorHumansPiperidinesProto-Oncogene Proteins c-bcl-2SulfonamidesAzetidinesBCL2 protein, humanBridged Bicyclo Compounds, HeterocycliccobimetinibPiperidinesProto-Oncogene Proteins c-bcl-2Sulfonamidesvenetoclax

Identifiers

PMID31123034
PMCPMC7049339
OpenAlexW2945831681

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC
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.