BET-directed PROTACs in triple negative breast cancer cell lines MDA-MB-231 and MDA-MB-436

Purpose: This study investigates whether the proliferation and migration of triple-negative breast cancer (TNBC) cell lines can be diminished by treating them with the bromodomain and extra-terminal domain (BET) inhibitor JQ1 and two BET-targeting PROTACs, ARV-771 and MZ1.

Methods: To assess the effects of the BET inhibitor and the two PROTACs on cell viability, migration, and protein expression, we conducted cytotoxicity tests, scratch migration assays, and Western blot proteome profiler arrays to analyze the expression of cancer-related proteins.

Results: JQ1 and the PROTACs MZ1 and ARV-771 significantly inhibited the growth and migration of the KRAS G13D-mutated MDA-MB-231 cells. In this cell line, the PROTACs reduced the residual expression of ERBB2/HER2, 3, and 4, which are critical for breast cancer cell proliferation, and the cells showed sensitivity to HER2 inhibitors. Conversely, the impact of the PROTACs on the protein expression in MDA-MB-436 cells primarily affected cytokines and their corresponding receptors.

Conclusion: The degradation of BET proteins by PROTACs exhibited notable anti-proliferative effects. The KRAS-mutated MDA-MB-231 cells, classified as low-HER2 expressing tumors, have a poorer prognosis compared to HER2-null patients. With the first oral PROTACs targeting tumor hormone receptors currently in clinical trials, this therapeutic approach is anticipated to become a significant strategy in the future treatment of TNBC.H