Abstract 4692: A novel ceramide synthase 2 agonist and its implication in triple-negative breast cancer therapy

Abstract Based on the biological/molecular markers, breast cancer can be classified into five subgroups: Luminal A (ER+/PR+/HER2-), Luminal B (ER+/PR-/HER2- or ER+/PR+/HER2+, triple-positive), ER-/PR-/HER2+, and ER-/PR-/HER2- (triple-negative). Significant progress has been made in treating hormone-responsive and HER2-expressing breast cancer. However, the targeted therapies are limited for triple-negative breast cancer (TNBC) due to lack of well-defined druggable targets. Additionally, all breast cancer subtypes can quickly develop resistance to current treatments. Thus, there is an urgent need for therapeutic strategies targeting pathways common to all subtypes, irrespective of receptor status. In this effort, we have synthesized a novel biisoquinoline-derivative, DH20931 (US Patent ID: US9914733B2) that induces cytotoxicity in breast cancer cells, including TNBC cells. The spatial molecular modeling and enzymatic assays show that DH20931 interacts with and stimulates ceramide synthase 2 (CerS2) activity, reduces the growth of hormone-responsive, HER2-expressing, and TNBC cells in monolayer and 3D spheroid culture models. DH20931 treatment increases the level of very long chain fatty acid (VLCFA) containing ceramides, induces lipotoxic endoplasmic reticulum (ER) stress, and ATF4/CHOP/PUMA pathway of apoptosis. Based on Swiss-ADME analysis, DH20931 possess all the properties of a druggable molecule and obeys the Lipinski-rule-of-five. Thus, DH20931 can be developed as a novel targeted therapeutic agent independent of ER, PR and HER2 status that potentially may reduce the morbidity and mortality for women with breast cancer. Citation Format: Hissah Alatawi, Nayeong Koo, Iqbal Mahmud, Haritha Nair, Amandeep Singh, Timothy J. Garrett, Arun K. Sharma, Sukwon Hong, Satya Narayan. A novel ceramide synthase 2 agonist and its implication in triple-negative breast cancer therapy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4692.