Evidence map›Paper›PMID 37992684›Full record

ArticleCell reports. Medicine2023

Allosteric SHP2 inhibition increases apoptotic dependency on BCL2 and synergizes with venetoclax in FLT3- and KIT-mutant AML.

Bogdan Popescu, Carlos Stahlhut, Theodore C Tarver, Sydney Wishner, Bianca J Lee, Cheryl A C Peretz, Cuyler Luck, Paul Phojanakong, Juan Antonio Camara Serrano, Henry Hongo and 7 more

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

Article in Cell reports. Medicine, 2023. 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
3.2field-weighted citation impact, top 7% 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.

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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

17 authors at 4 institutions in 2 countries.

Bogdan PopescuDivision of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
Carlos StahlhutRevolution Medicines, Inc., Redwood City, CA, USA.
Theodore C TarverDivision of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Sydney WishnerDivision of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Bianca J LeeRevolution Medicines, Inc., Redwood City, CA, USA.
Cheryl A C PeretzDepartment of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Cuyler LuckDepartment of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Paul PhojanakongPreclinical Therapeutics Core, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Juan Antonio Camara SerranoPreclinical Therapeutics Core, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Henry HongoHelen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Jose M RiveraHelen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Simayijiang XirenayiHelen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
John A ChukinasDivision of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Veronica SteriPreclinical Therapeutics Core, Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Sarah K TasianDivision of Oncology, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Elliot StieglitzDepartment of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Catherine C SmithDivision of Hematology/Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. Electronic address: catherine.smith@ucsf.edu.
University of California, San Francisco · USChildren's Hospital of Philadelphia · USRevolution Medicines (United States) · USCarol Davila University of Medicine and Pharmacy · RO

Funding

Translational InformaticsP30CA082103 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Kate Taylor Shumate · 1999 to 2026
$209.7M
Restorative practice in repairing harm and promoting safe and inclusive practices in the laboratory.T32GM136547 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Adrian Erlebacher, Anita Sil · 2020 to 2026
$4.5M
UCSF Paul Calabresi K12 Career Development Program in Clinical OncologyK12CA260225 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI BERGSLAND, EMILY K, BIVONA, TREVER G · 2021 to 2025
$2.6M
Investigating the mechanism of SHP2 and BCL2 Inhibition in Acute Myeloid Leukemia (AML)R01CA277031 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Catherine Choy Smith · 2023 to 2026
$1.9M
NCI NIH HHS K12 CA260225NCI NIH HHS P30 CA082103NCI NIH HHS R01 CA277031NIGMS NIH HHS T32 GM136547
6 · The paper itself

Abstract

Mutations in the receptor tyrosine kinases (RTKs) FLT3 and KIT are frequent and associated with poor outcomes in acute myeloid leukemia (AML). Although selective FLT3 inhibitors (FLT3i) are clinically effective, remissions are short-lived due to secondary resistance characterized by acquired mutations constitutively activating the RAS/MAPK pathway. Hereby, we report the pre-clinical efficacy of co-targeting SHP2, a critical node in MAPK signaling, and BCL2 in RTK-driven AML. The allosteric SHP2 inhibitor RMC-4550 suppresses proliferation of AML cell lines with FLT3 and KIT mutations, including cell lines with acquired resistance to FLT3i. We demonstrate that pharmacologic SHP2 inhibition unveils an Achilles' heel of RTK-driven AML, increasing apoptotic dependency on BCL2 via MAPK-dependent mechanisms, including upregulation of BMF and downregulation of MCL1. Consequently, RMC-4550 and venetoclax are synergistically lethal in AML cell lines and in clinically relevant xenograft models. Our results provide mechanistic rationale and pre-clinical evidence for co-targeting SHP2 and BCL2 in RTK-driven AML.

Indexed as

ApoptosisLeukemia, Myeloid, AcuteBridged Bicyclo Compounds, HeterocyclicCell Line, Tumorfms-Like Tyrosine Kinase 3HumansProtein Kinase InhibitorsProto-Oncogene Proteins c-bcl-2SulfonamidesBCL2 protein, humanBridged Bicyclo Compounds, HeterocyclicFLT3 protein, humanfms-Like Tyrosine Kinase 3Protein Kinase InhibitorsProto-Oncogene Proteins c-bcl-2Sulfonamidesvenetoclaxacute myeloid leukemiaapoptosiscancerdrug synergyFLT3SHP2targeted therapies

Identifiers

PMID37992684
PMCPMC10694768
OpenAlexW4388951907

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
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.