Evidence map›Paper›PMID 34331013›Full record

ArticleOncogene2021

Synergistic melanoma cell death mediated by inhibition of both MCL1 and BCL2 in high-risk tumors driven by NF1/PTEN loss.

Shuning He, Mark W Zimmerman, Hillary M Layden, Alla Berezovskaya, Julia Etchin, Megan W Martel, Grace Thurston, Chang-Bin Jing, Ellen van Rooijen, Charles K Kaufman and 5 more

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

Article in Oncogene, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
0.9field-weighted citation impact, top 27% 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

5 citing papers in PubMed, 13 citations in OpenAlex.

  1. Article
  2. Article
  3. Article
  4. Article
  5. One Host-Multiple Applications: Zebrafish (International journal of molecular sciences · 2022
    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

15 authors at 5 institutions in 2 countries.

Shuning HeDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. shuning_he@dfci.harvard.edu.ORCID http://orcid.org/0000-0003-0747-2425
Mark W ZimmermanDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0003-2489-3889
Hillary M LaydenDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.ORCID http://orcid.org/0000-0001-8583-620X
Alla BerezovskayaDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Julia EtchinDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Megan W MartelDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Grace ThurstonDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Chang-Bin JingDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Ellen van RooijenStem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA, USA.
Charles K KaufmanStem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA, USA.
Scott J RodigDepartment of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
Leonard I ZonStem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA, USA.ORCID http://orcid.org/0000-0003-0860-926X
E Elizabeth PattonMRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
Marc R MansourDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. m.mansour@ucl.ac.uk.ORCID http://orcid.org/0000-0001-6835-3791
A Thomas LookDepartment of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Thomas_Look@dfci.harvard.edu.ORCID http://orcid.org/0000-0001-7851-8617
Harvard University · USHoward Hughes Medical Institute · USBrigham and Women's Hospital · USCancer Research UK · GBInstitute of Genetics and Cancer · GB

Funding

Transcriptional mechanisms and melanomaP01CA163222 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI Kai W Wucherpfennig · 2013 to 2026
$25.3M
Cancer Biology in the ZebrafishR01CA103846 · NCI · CHILDREN'S HOSPITAL BOSTON · PI ZON, LEONARD IRA · 2003 to 2022
$7.5M
Mechanisms and Vulnerabilities of Aberrant Transcriptional Enhancers in CancerR35CA210064 · NCI · DANA-FARBER CANCER INST · PI LOOK, A. THOMAS · 2016 to 2022
$7.3M
NCI NIH HHS P01 CA163222NCI NIH HHS R01 CA103846NCI NIH HHS R35 CA210064
6 · The paper itself

Abstract

Melanomas driven by loss of the NF1 tumor suppressor have a high risk of treatment failure and effective therapies have not been developed. Here we show that loss-of-function mutations of nf1 and pten result in aggressive melanomas in zebrafish, representing the first animal model of NF1-mutant melanomas harboring PTEN loss. MEK or PI3K inhibitors show little activity when given alone due to cross-talk between the pathways, and high toxicity when given together. The mTOR inhibitors, sirolimus, everolimus, and temsirolimus, were the most active single agents tested, potently induced tumor-suppressive autophagy, but not apoptosis. Because addition of the BCL2 inhibitor venetoclax resulted in compensatory upregulation of MCL1, we established a three-drug combination composed of sirolimus, venetoclax, and the MCL1 inhibitor S63845. This well-tolerated drug combination potently and synergistically induces apoptosis in both zebrafish and human NF1/PTEN-deficient melanoma cells, providing preclinical evidence justifying an early-stage clinical trial in patients with NF1/PTEN-deficient melanoma.

Indexed as

AnimalsBridged Bicyclo Compounds, HeterocyclicCell Line, TumorCell ProliferationCell SurvivalDrug SynergismEverolimusHumansLoss of Function MutationMelanomaMTOR InhibitorsMyeloid Cell Leukemia Sequence 1 ProteinNeurofibromin 1Proto-Oncogene Proteins c-bcl-2PTEN PhosphohydrolasePyrimidinesBCL2 protein, humanBridged Bicyclo Compounds, HeterocyclicEverolimusMCL1 protein, humanMTOR InhibitorsMyeloid Cell Leukemia Sequence 1 ProteinNeurofibromin 1NF1 protein, humanProto-Oncogene Proteins c-bcl-2PTEN PhosphohydrolasePTEN protein, humanPyrimidinesS63845SirolimusSulfonamidestemsirolimusThiophenesvenetoclax

Identifiers

PMID34331013
PMCPMC8460449
OpenAlexW3185957404

What OpenQuestion holds

Textmetadata
LicenceCC BY
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.