Abstract P49: PROTAC A1874: A Potential Targeted Therapy for Breast Cancer

Abstract

Abstract Background PROteolysis TArgeting Chimera (PROTAC) A1874 is a heterobifunctional structured compound consisting of a BRD4-recognizing ligand and an MDM2-recognizing ligand that functions to degrade BRD4 via the ubiquitin-proteasome system. A1874 also plays a dual role in downregulating downstream BRD4 regulator, MYC, and stabilizing p53 within nanomolar concentrations. This PROTAC thus presents itself as a potential therapy for both estrogen-receptor positive (ER+) and triple-negative breast cancer (TNBC) subtypes, which typically harbors wild-type p53 and are associated with MYC overexpression respectively. Thus, this study aims to 1) investigate the anti-oncogenic effects and mechanism of A1874 and 2) its effect in combination with existing therapies in several breast cancer (BC) cell lines. Methods A panel of BC cell lines harboring different p53 status were tested for their sensitivity to A1874. Several functional assays were conducted to determine the anti-oncogenic effects of A1874. Bliss scores were calculated using SynergyFinder to determine the interaction of drugs in combination with A1874. Results BC cell lines with p53 WT status showed significantly lower IC50 sensitivity to A1874 in the nanomolar range compared to those with p53 mutation, which exhibited sensitivity in the micromolar range regardless of subtypes. Moreover, it is effective in Tam-resistant ER+, p53 WT cells. A1874 exclusively degrades BRD4 in p53 WT cells and causes G1 arrest, inhibition of colony formation, proliferation, and migration. Knockdown of MDM2 or TP53, and lentiviral transduction of p53 mutant plasmid resulted in significant reduction in sensitivity to A1874 in p53 WT cell lines and abrogate its BRD4-degrading effect. Combination of A1874 with the mutant p53 reactivating drug, PRIMA-1, synergistically resensitize mutant p53 cells to the cytotoxic effect of A1874 across subtypes. Conclusions Our results highlight a promising potential of PROTAC A1874 as a therapeutic drug in breast cancer, specifically the ER+ subtype which typically retains its p53 WT status. Citation Format: Charlie Marvalim, Arpita Datta, Serena Bee Kee Seah, Edward Kai-Hua Chow, Soo Chin Lee. PROTAC A1874: A Potential Targeted Therapy for Breast Cancer [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P49.