Goerg Alina, Piendl Gerhard, Albert Veruschka, Ortmann Olaf, Wege Anja Kathrin, Brockhoff Gero
Department of Gynecology and Obstetrics, University Medical Center Regensburg, Franz-Josef-Strauß-Allee 11, 93053, Regensburg, Germany.
Bavarian Cancer Research Center (BZKF), Regensburg, Germany.
BMC Cancer. 2025 Jun 1;25(1):978. doi: 10.1186/s12885-025-14361-z.
The human double minute 2 homolog hdm2, alias mdm2, is the main negative-regulator of the tumor suppressor p53. In that capacity, mdm2 is a promising but not yet utilized molecular target for the treatment of breast cancer, however, its inhibition by small molecules is rather inappropriate. Instead, mdm2 degradation by PROteolysis TArgeting Chimeras (PROTAC) is expected to be highly specific, to exhibit pronounced efficiency and minimal side effects. Moreover, there is profound evidence that mdm2-specific PROTAC degraders are efficient even in tumor cells harboring p53 loss-of-function mutations.
We comparatively treated p53 wildtype / abemaciclib-sensitive and -resistant MCF-7, as well as p53-mutated T-47D estrogen receptor-positive breast cancer cells in-vitro with the mdm2 inhibitor AMG-232 and an mdm2 PROTAC degrader. The molecular signaling as a function of mdm2 inhibition and degradation was assessed and cell viability and cell cycle kinetics were monitored. In addition, potential PROTAC effects on the expression of immune-related markers MHC-I, MHC-II, PD-L1, PD-L2, and CD276 were determined.
PROTAC treatment considerably attenuated cell proliferations and was superior to mdm2 inhibition in p53 wildtype and even in p53-mutated cells. Proliferation-associated pathways were significantly but differentially affected, including p73, retinoblastoma protein, and the transcription factor E2F1. MHC-I and CD276 were significantly downregulated.
The data reveal deeper insight into PROTAC-induced molecular mechanisms in luminal breast cancer cells with and without p53 mutations. The study provides the basis to evaluate the therapeutic applicability of anti-mdm2 PROTAC degraders in an appropriate preclinical in-vivo setting, for example in humanized tumor mice.
The online version contains supplementary material available at 10.1186/s12885-025-14361-z.
人类双微体2同源物hdm2，别名mdm2，是肿瘤抑制因子p53的主要负调节因子。基于此，mdm2是治疗乳腺癌一个有前景但尚未被利用的分子靶点，然而，小分子对其抑制作用并不合适。相反，通过蛋白酶靶向嵌合体（PROTAC）降解mdm2有望具有高度特异性、显著疗效和最小副作用。此外，有充分证据表明，mdm2特异性PROTAC降解剂即使在携带p53功能丧失突变的肿瘤细胞中也有效。
我们在体外分别用mdm2抑制剂AMG-232和一种mdm2 PROTAC降解剂处理p53野生型/对阿贝西利敏感和耐药的MCF-7细胞，以及p53突变的T-47D雌激素受体阳性乳腺癌细胞。评估了作为mdm2抑制和降解函数的分子信号传导，并监测了细胞活力和细胞周期动力学。此外，还测定了PROTAC对免疫相关标志物MHC-I、MHC-II、PD-L1、PD-L2和CD276表达的潜在影响。
PROTAC处理显著减弱了细胞增殖，在p53野生型细胞甚至p53突变细胞中，其效果优于mdm2抑制。增殖相关途径受到显著但不同的影响，包括p73、视网膜母细胞瘤蛋白和转录因子E2F1。MHC-I和CD276显著下调。
这些数据揭示了对有或无p53突变的管腔型乳腺癌细胞中PROTAC诱导的分子机制的更深入见解。该研究为在合适的临床前体内环境（例如人源化肿瘤小鼠）中评估抗mdm2 PROTAC降解剂的治疗适用性提供了基础。
在线版本包含可在10.1186/s12885-025-14361-z获取的补充材料。
