Evidence map›Paper›PMID 41023593›Full record

ArticleMolecular medicine (Cambridge, Mass.)2025

Selective inhibition of BRAF and CRAF sensitizes NF1-deficient malignant peripheral nerve sheath tumors to MEK inhibitors.

Jiawan Wang, Arnab Sarkar, Natalia Garcia, Lindy Zhang, Ana Calizo, Alla Lisok, Katia Campos, Funan He, Nishanth Punjaala, Teresa Marple and 6 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular medicine (Cambridge, Mass.), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
–field-weighted citation impact
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

1 citing paper in PubMed.

  1. Article
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

16 authors.

Jiawan WangDivision of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Arnab SarkarGreehey Children's Cancer Research Institute, and Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, TX, USA.
Natalia GarciaGreehey Children's Cancer Research Institute, and Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, TX, USA.
Lindy ZhangDivision of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Ana CalizoDivision of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Alla LisokDivision of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Katia CamposGreehey Children's Cancer Research Institute, and Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, TX, USA.
Funan HeGreehey Children's Cancer Research Institute, and Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, TX, USA.
Nishanth PunjaalaGreehey Children's Cancer Research Institute, and Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, TX, USA.
Teresa MarpleGreehey Children's Cancer Research Institute, and Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, TX, USA.
Kai PollardDivision of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Siyuan ZhengGreehey Children's Cancer Research Institute, and Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, TX, USA.
Calixto-Hope G LucasDepartment of Pathology/ Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Vesselina G CookeOncology Drug Discovery, Novartis BioMedical Research, Cambridge, MA, USA.
Christine A PratilasDivision of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. cpratil1@jhmi.edu.
Angelina V VasevaGreehey Children's Cancer Research Institute, and Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, TX, USA. vaseva@ohsu.edu.

Funding

TISSUE CULTURE---COREP30CA054174 · NCI · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · PI LUZHE SUN · 1991 to 2026
$59.1M
LAB RESEARCH TRAINING IN PEDIATRIC ONCOLOGY-HEMATOLOGYT32CA060441 · NCI · JOHNS HOPKINS UNIVERSITY · PI ALAN D FRIEDMAN · 1993 to 2026
$14.9M
Advancing RAS pathway targeted therapy in NF1-MPNST: effects of SHP2 and CDK4/6 inhibitors on the tumor and the tumor immune microenvironmentR01CA269625 · NCI · JOHNS HOPKINS UNIVERSITY · PI Christine Anne Pratilas · 2023 to 2026
$2.3M
Illumina NovaSeq 6000 Sequencing SystemS10OD030311 · OD · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · PI LAI, ZHAO · 2021 to 2021
$600k
NCI NIH HHS P30 CA054174NCI NIH HHS R01 CA269625NCI NIH HHS T32 CA060441NIH HHS S10 OD030311
6 · The paper itself

Abstract

backgroundTreatment for patients with malignant peripheral nerve sheath tumors (MPNST) is an unmet clinical need. Loss of NF1 in MPNST leads to hyperactivation of RAS, however little is known about relevant downstream oncogenic signaling through RAF paralogs and effective targeted therapies in MPNST are still lacking.

methodsConditional gene expression, CRISPR-CAS9, and shRNA-mediated knockdown were used to perform gain/loss-of-function experiments to explore the effect of reconstituting the GTPase-activating protein-related domain of NF1 or knockdown of A/B/CRAF kinases on ERK signaling output and MPNST cell growth. Colony formation, cell proliferation and live cells imaging assays were performed to assess cell growth in response to genetic manipulations or drug treatments. Pathway enrichment analysis on RNA sequencing following drug perturbation, efficacy studies in cell-line-derived and patient-derived xenograft models, and immunoblotting/immunohistochemistry were conducted to assess tumor growth and ERK pathway activity in cells or in pharmacodynamic analyses of tumor xenografts.

resultsNF1 loss activates RAS/ERK signaling through B/CRAF, and cell growth and ERK signaling of NF1-MPNST are dependent on B/CRAF, but not ARAF. Genetic or pharmacological inhibition of B/CRAF using a paralog-selective RAF inhibitor (RAFi) significantly potentiates MEK inhibitor (MEKi) treatment through more effective suppression of ERK signaling and proliferation. This is shown in multiple traditional and patient-derived cell line and xenograft models, including those with acquired resistance to MEKi.

conclusionsThese findings contribute preclinical evidence that the combination of paralog-selective B/CRAFi and MEKi is effective in NF1-MPNST and can overcome resistance to single agent MEKi.

Indexed as

Nerve Sheath NeoplasmsNeurofibromin 1Protein Kinase InhibitorsProto-Oncogene Proteins B-rafProto-Oncogene Proteins c-rafAnimalsCell Line, TumorCell ProliferationFemaleHumansMiceXenograft Model Antitumor AssaysBRAF protein, humanNeurofibromin 1NF1 protein, humanProtein Kinase InhibitorsProto-Oncogene Proteins B-rafProto-Oncogene Proteins c-rafMalignant peripheral nerve sheath tumorMEKNeurofibromatosis type 1RAFRAS

Identifiers

PMID41023593
PMCPMC12482338

What Socratic holds

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LicenceCC BY
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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 Socratic graph.