Targeting MDM4 as a Novel Therapeutic Approach in Prostate Cancer Independent of p53 Status

Mejia-Hernandez, JO; Raghu, D; Caramia, F; Clemons, N; Fujihara, K; Riseborough, T; Teunisse, A; Jochemsen, AG; Abrahmsen, L; Blandino, G; Russo, A; Gamell, C; Fox, SB; Mitchell, C; Takano, EA; Byrne, D; Miranda, PJ; Saleh, R; Thorne, H; Sandhu, S; Williams, SG; Keam, SP; Haupt, Y; Haupt, S

Author(s): Mejia-Hernandez, JO; Raghu, D; Caramia, F; Clemons, N; Fujihara, K; Riseborough, T; Teunisse, A; Jochemsen, AG; Abrahmsen, L; Blandino, G; Russo, A; Gamell, C; Fox, SB; Mitchell, C; Takano, EA; Byrne, D; Miranda, PJ; Saleh, R; Thorne, H; Sandhu, S; Williams, SG; Keam, SP; Haupt, Y; Haupt, S;
Details: Publication Year 2022-08-16,Volume 14,Issue #16,Page 3947
Journal Title: Cancers
Publication Type: Research article
Abstract: Metastatic prostate cancer is a lethal disease in patients incapable of responding to therapeutic interventions. Invasive prostate cancer spread is caused by failure of the normal anti-cancer defense systems that are controlled by the tumour suppressor protein, p53. Upon mutation, p53 malfunctions. Therapeutic strategies to directly re-empower the growth-restrictive capacities of p53 in cancers have largely been unsuccessful, frequently because of a failure to discriminate responses in diseased and healthy tissues. Our studies sought alternative prostate cancer drivers, intending to uncover new treatment targets. We discovered the oncogenic potency of MDM4 in prostate cancer cells, both in the presence and absence of p53 and also its mutation. We uncovered that sustained depletion of MDM4 is growth inhibitory in prostate cancer cells, involving either apoptosis or senescence, depending on the cell and genetic context. We identified that the potency of MDM4 targeting could be potentiated in prostate cancers with mutant p53 through the addition of a first-in-class small molecule drug that was selected as a p53 reactivator and has the capacity to elevate oxidative stress in cancer cells to drive their death.
Publisher: MDPI
Keywords: Apr-246; Mdm4; Mdmx; Tp53; Xi-011; eprenetapopt; mutant p53; p53; prostate cancer
Department(s): Laboratory Research; Pathology; Medical Oncology; Radiation Oncology
PubMed ID: 36010941
Publisher's Version: https://doi.org/10.3390/cancers14163947
Open Access at Publisher's Site: https://doi.org/10.3390/cancers14163947
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-01-31 07:02:47

Last Modified: 2025-01-31 07:03:46