Targeted MDM2 degradation reveals a new vulnerability for p53 inactivated triple negative breast cancer.
Clare M AdamsRamkrishna MitraYou-Cai XiaoPeter MichenerJuan PalazzoAllen ChaoJitendra GourJoel A CasselJoseph M SalvinoChristine M EischenPublished in: Cancer discovery (2023)
Triple negative breast cancers (TNBC) frequently inactivate p53, increasing their aggressiveness and therapy resistance. We identified an unexpected protein vulnerability in p53-inactivated TNBC and designed a new PROTAC to target it. Our PROTAC selectively targets MDM2 for proteasome-mediated degradation with high-affinity binding and VHL recruitment. MDM2 loss in p53 mutant/deleted TNBC cells in 2D/3D culture and TNBC patient explants, including relapsed tumors, causes apoptosis, while sparing normal cells. Our MDM2-PROTAC is stable in vivo, and treatment of TNBC xenograft-bearing mice demonstrates tumor on-target efficacy with no toxicity to normal cells, significantly extending survival. Transcriptomic analyses revealed upregulation of p53 family target genes. Investigations showed activation and a required role for TAp73 to mediate MDM2-PROTAC-induced apoptosis. Our data, challenging the current MDM2/p53 paradigm, show MDM2 is required for p53-inactivated TNBC cell survival, and PROTAC-targeted MDM2 degradation is an innovative potential therapeutic strategy for TNBC and superior to existing MDM2 inhibitors.
Keyphrases
- induced apoptosis
- endoplasmic reticulum stress
- oxidative stress
- cell cycle arrest
- signaling pathway
- climate change
- cell death
- stem cells
- cancer therapy
- acute myeloid leukemia
- mesenchymal stem cells
- electronic health record
- single cell
- diffuse large b cell lymphoma
- gene expression
- young adults
- binding protein
- genome wide identification