Pharmacological Inhibition of MDM2 Induces Apoptosis in p53-Mutated Triple-Negative Breast Cancer

Triple-negative breast Cancer (TNBC) represents the most aggressive breast carcinoma subtype lacking efficient therapeutic options. A promising approach in Cancer treatment is the pharmacological inhibition of murine double minute 2 (MDM2)-p53 interaction inducing Apoptosis in p53 wild-type tumors. However, the role of MDM2 in TNBC with primarily mutant p53 is not well understood. We here selected the clinical-stage MDM2 inhibitors Idasanutlin and Milademetan and investigated their anti-tumoral effects in TNBC. When we analyzed anti-tumor activity in the TNBC cell lines MDA-MB-231, MDA-MB-436, and MDA-MB-468, cellular viability was efficiently reduced, with half maximal inhibitory concentration (IC₅₀) values ranging between 2.00 and 7.62 µM being up to 11-fold lower compared to the well-characterized non-clinical-stage MDM2 Inhibitor Nutlin-3a. Furthermore, Caspase-3/7 activity was efficiently induced. Importantly, the IC₅₀ values for MDM2 inhibition were equally observed in HCT116 p53^+/+ or HCT116 p53^-/- cells. Finally, the IC₅₀ was significantly higher in non-malignant MCF-10A cells than in TNBC cells. Taken together, Idasanutlin and Milademetan show a potent anti-tumor activity in TNBC Cell Culture models by efficiently inducing tumor cell death via Apoptosis. This effect was observed despite an inactivating p53 mutation and was apparently independent of p53 expression. Our data suggest that MDM2 is a promising target in TNBC and clinical-stage MDM2 inhibitors should be further evaluated for their potential therapeutic application.

MDM2 inhibitor; apoptosis; p53 mutation; triple-negative breast cancer.