Evidence map›Paper›PMID 40894709›Full record

ArticlebioRxiv : the preprint server for biology2025

CerS2 is a druggable target in triple-negative breast cancer.

Hissah Alatawi, Haritha H Nair, Lingbao Ai, Iqbal Mahmud, Abhishek Gour, Amandeep Singh, Doohyun Baek, Bowen Yan, Chandra K Maharjan, Weizhou Zhang and 10 more

Abstract readPreprint
PubMed Full text at PMC Publisher
In one paragraph

Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing 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

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

20 authors.

Hissah AlatawiDepartment of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610.
Haritha H NairDepartment of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610.
Lingbao AiDepartment of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610.
Iqbal MahmudDepartment of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610.
Abhishek GourDepartment of Pharmaceutics, College of Medicine, University of Florida, Gainesville, FL 32610.
Amandeep SinghDepartment of Pharmacology, Penn State Cancer Institute, Hersey, PA 17033.
Doohyun BaekDepartment of Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706.
Bowen YanDepartment of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL 32610.
Chandra K MaharjanDepartment of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610.
Weizhou ZhangDepartment of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610.ORCID 0000-0002-8236-0346
Brian K LawDepartment of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL 32610.
Maria Zajac-KayeDepartment of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610.
Christopher VulpeDepartment of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610.
Olga A GuryanovaDepartment of Pharmacology and Therapeutics, College of Medicine, University of Florida, Gainesville, FL 32610.
Arun K SharmaDepartment of Pharmacology, Penn State Cancer Institute, Hersey, PA 17033.
Timothy J GarrettDepartment of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610.
Abhisheak SharmaDepartment of Pharmaceutics, College of Medicine, University of Florida, Gainesville, FL 32610.
Coy D HeldermonDepartment of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610.
Sukwon HongDepartment of Chemistry, University of Florida, Gainesville, FL 32611.
Satya NarayanDepartment of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610.ORCID 0000-0001-7080-8900

Funding

University of Florida Health Cancer Center Support GrantP30CA247796 · NCI · UNIVERSITY OF FLORIDA · PI DIETMAR W SIEMANN · 2023 to 2026
$10.9M
Proteolysis-targeting chimera against BCL-XL inhibits breast cancer metastasisR01CA260239 · NCI · UNIVERSITY OF FLORIDA · PI ZHANG, WEIZHOU · 2021 to 2025
$2.5M
Proteolysis targeting chimera against nuclear receptor NR4A1 for melanoma therapyR01CA290792 · NCI · UNIVERSITY OF FLORIDA · PI Keiran Smalley, Weizhou Zhang · 2024 to 2026
$2.0M
The role of DNMT3A mutations in clonal heterogeneity and evolution of hematopoiesisR01DK121831 · NIDDK · UNIVERSITY OF FLORIDA · PI GURYANOVA, OLGA A · 2019 to 2023
$1.7M
Regulation of Death Receptor 5 folding and apoptotic signaling by AGR2R21CA252400 · NCI · UNIVERSITY OF FLORIDA · PI LAW, BRIAN K. · 2020 to 2020
$389k
HER1-3 and Death Receptor protein folding as therapeutic vulnerabilitiesR21CA277485 · NCI · UNIVERSITY OF FLORIDA · PI LAW, BRIAN K. · 2023 to 2024
$375k
NCI NIH HHS P30 CA247796NCI NIH HHS R01 CA260239NCI NIH HHS R01 CA290792NCI NIH HHS R21 CA252400NCI NIH HHS R21 CA277485NIDDK NIH HHS R01 DK121831
6 · The paper itself

Abstract

Triple-negative breast cancer (TNBC) remains a significant clinical challenge due to its aggressive nature and lack of effective targeted therapies. The enzyme ceramide synthase 2 (CerS2), which synthesizes pro-apoptotic very long-chain ceramides (VLCCs), represents a promising therapeutic target. Here, we identify and characterize DH20931, a novel, first-in-class small-molecule agonist of CerS2. We demonstrate that DH20931 directly activates CerS2 with nanomolar potency, leading to significant VLCC accumulation in breast cancer cells. This lipotoxic event induces endoplasmic reticulum (ER) stress and triggers apoptosis via the canonical ATF4/CHOP/PUMA signaling pathway. Mechanistically, we uncover a novel interaction between CerS2 and the ER calcium channel, Inositol 1,4,5-trisphosphate receptor 1 (IP3R1). We demonstrate that DH20931 promotes this interaction, enhancing ER-mitochondria proximity and facilitating a CerS2-dependent flux of calcium (Ca

Indexed as

apoptosiscalcium signalingceramide synthase 2 (CerS2)DH20931ER stressIP3R1mitochondriatargeted therapyTriple-negative breast cancer (TNBC)very long chain ceramides (VLCC)

Identifiers

PMID40894709
PMCPMC12393413

What OpenQuestion holds

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Registered trials

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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.