Related Experiment Video
Updated: Sep 9, 2025
Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures
Published on: December 26, 2016
CerS2 is a druggable target in triple-negative breast cancer
Hissah Alatawi1,2, Haritha H Nair1,3, Lingbao Ai4
1Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610.
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 (Ca2+) from the ER into mitochondria. This subsequent mitochondrial Ca2+ overload serves as a critical trigger for apoptosis. In preclinical evaluations, DH20931 potently inhibited the growth of TNBC cells in 2D and 3D cultures and significantly suppressed tumor progression in orthotopic and patient-derived xenograft (PDX) models, all while exhibiting a favorable safety profile. Our findings validate CerS2 as a druggable target in TNBC and establish a novel therapeutic strategy that leverages a coordinated attack on cancer cells through ER stress and calcium-mediated mitochondrial dysfunction.
Insights
A new drug, DH20931, activates ceramide synthase 2 (CerS2) to induce cell death in triple-negative breast cancer. This novel therapy targets ER stress and mitochondrial calcium overload, showing significant preclinical efficacy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Triple-negative breast cancer (TNBC) presents a significant therapeutic challenge due to its aggressive nature and limited targeted treatment options.
- Ceramide synthase 2 (CerS2), an enzyme synthesizing pro-apoptotic very long-chain ceramides (VLCCs), is a potential therapeutic target for TNBC.
Purpose of the Study:
- To identify and characterize DH20931, a novel small-molecule agonist of CerS2.
- To elucidate the mechanism by which DH20931 induces apoptosis in breast cancer cells.
- To evaluate the preclinical efficacy and safety of DH20931 against TNBC.
Main Methods:
- In vitro biochemical assays to assess CerS2 activation and VLCC synthesis.
- Cell-based assays to measure ER stress, apoptosis signaling (ATF4/CHOP/PUMA), and calcium flux.
- In vivo studies using TNBC cell lines in orthotopic and patient-derived xenograft models.
Main Results:
- DH20931 directly activates CerS2 with nanomolar potency, increasing VLCC levels in breast cancer cells.
- DH20931 induces ER stress and apoptosis via the ATF4/CHOP/PUMA pathway.
- DH20931 promotes a novel interaction between CerS2 and IP3R1, leading to mitochondrial calcium overload and apoptosis.
- DH20931 demonstrated potent inhibition of TNBC growth in preclinical models with a favorable safety profile.
Conclusions:
- CerS2 is a druggable target for TNBC treatment.
- DH20931 represents a first-in-class therapeutic strategy for TNBC by inducing lipotoxicity, ER stress, and mitochondrial calcium overload.
- Targeting CerS2 offers a novel approach to combatting aggressive breast cancer.
More Related Videos
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:34Inhibition of Cdk Activity
02:56Treatment Resistant Cancers