bims-midomi Biomed News
on MDM2 and mitochondria
Issue of 2025–06–08
seven papers selected by
Gavin McStay, Liverpool John Moores University
  1. MDM2 inhibitors in sarcomas: results and next steps.
  2. Targeted Degradation of Mutant p53 Reverses the Pro-oncogenic Dominant-Negative Effect.
  3. APG-115 synergizes with bortezomib to induce apoptosis in cervical cancer cells.
  4. Mdm2 targeting via PROteolysis TArgeting Chimeras (PROTAC) is efficient in p53 wildtype, p53-mutated, and abemaciclib-resistant estrogen receptor-positive cell lines and superior to mdm2 inhibition.
  5. Real-world survival outcomes and MDM2 prevalence in US patients with metastatic dedifferentiated liposarcoma.
  6. Penicilazaphilone C triggers ferroptosis in triple-negative breast cancer cells via the MDM2/p53/SLC7 A11/GPX4 pathway.
  7. Lipid Droplet-Organized MDM2-Mediated P53 Degradation: A Metabolic Switch Governing Diet-Driven Tumor Progression.
  1. Curr Opin Oncol. 2025 Jul 01. 37(4): 324-330
    MDM2 inhibitors in sarcomas: results and next steps.
    Ilaria Tortorelli, Andrea Napolitano, Yuhong Zhou, Paul Huang, Robin L Jones.
       PURPOSE OF REVIEW: Murine double minute 2 (MDM2) is an oncogene that plays a crucial role in regulating the activity of the tumor suppressor protein p53. By binding to p53, MDM2 promotes its degradation, thus promoting the malignant proliferation. The MDM2-p53 interaction has thus generated interest as a therapeutic target, particularly in some sarcomas characterized by the amplification of the MDM2 gene. In this manuscript, we provide an overview of the current and emerging targeted therapies for MDM2-amplified sarcomas.
    RECENT FINDINGS: Although several agents have been developed with promising results in preclinical studies, these molecules have failed to show conclusive benefit in clinical trials. Nevertheless, the MDM2-p53 pathway inhibition remains an area of ongoing investigation, including the development of novel inhibitors and combination strategies.
    SUMMARY: In the era of precision medicine, there is an unmet need for new effective therapies in patients with inoperable/metastatic sarcomas. In some histotypes, MDM2 is overexpressed due to gene amplification, leading to a reduced p53 activity and then in oncogenic transformation. By blocking the activity of MDM2, p53 function can be restored, potentially leading to tumor cell death. However, further research is needed to optimize the translation of MDM2 inhibitors into the clinical setting.
    Keywords:  MDM2; clinical trials; dedifferentiated liposarcoma; intimal sarcoma; osteosarcoma; p53; sarcomas
    DOI:  https://doi.org/10.1097/CCO.0000000000001146
  2. Cancer Res. 2025 Jun 02. 85(11): 1955-1956
    Targeted Degradation of Mutant p53 Reverses the Pro-oncogenic Dominant-Negative Effect.
    Jovanka Gencel-Augusto, Guillermina Lozano.
      p53 is a transcription factor that functions as a tumor suppressor and the active unit of which is a tetramer. Nearly all cancers inactivate the p53 pathway, primarily through missense mutations in TP53. Most mutant p53 proteins lose their function and often exhibit increased protein stability. In addition to this loss of function, mutant p53 can drive oncogenicity through a dominant-negative effect by forming mixed tetramers with wild-type (WT) p53 to inhibit its activity. The study in this issue of Cancer Research by Klemm and colleagues provides definitive evidence for the mechanism by which mutant p53 inactivates WT p53 function. The p53R248Q mutant has a longer half-life than WT p53, resulting in an approximate ratio of 3 or 4 mutant molecules to every WT molecule. This imbalance facilitates the dominant-negative effect, which can be overcome either by exogenously increasing WT p53 levels or by selectively degrading mutant p53. In experiments whereby mutant p53 was degraded using a degron-tagged construct combined with iberdomide as a molecular glue, remarkable therapeutic efficacy was observed when this approach was used in combination with an MDM2 inhibitor. This work paves the way for therapeutic strategies that aim to degrade mutant p53 proteins in cases in which a WT TP53 allele is retained. See related article by Klemm et al., p. 1978.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-1054
  3. Anticancer Drugs. 2025 Jun 03.
    APG-115 synergizes with bortezomib to induce apoptosis in cervical cancer cells.
    Chuanyue Sun, Xueqiong Meng, Xiaoxi Cui, Shihao Liang, Jie Sun, Binghui Zhang, Yanhong Cui, Yinzhen Zhao, Ning Chen, Kangli Tian, Yixiang Chen.
      Despite significant advancements in vaccination, screening, and therapeutic strategies have substantially reduced cervical cancer incidence, effective treatment for this disease remains a major clinical challenge. This study reveals that APG-115, a murine double minute 2 (MDM2) inhibitor, upregulates the transcription and expression of MDM2, p53, and p21, effectively inhibiting cell proliferation and inducing apoptosis in cervical cancer cells. Mechanistically, APG-115 suppresses the activation of the AKT and ERK signaling pathways and reduces the expression of antiapoptotic proteins BCL-2, BCL-xL, and MCL-1, while promoting the expression of pro-apoptotic proteins BAK, BAX, and BIM. Notably, the combination of APG-115 with bortezomib enhances p53 and p21 expression, synergistically induces cell apoptosis. In the cervical cancer xenograft models, APG-115 and bortezomib significantly downregulated the expression of Ki67 and BCL-2 while markedly increasing p21 protein levels, effectively suppressing tumor growth and inducing apoptosis. The combination further amplified the effects on Ki67, BCL-2, and p21 expression, leading to enhanced tumor growth inhibition. In summary, this study demonstrates that APG-115 exerts antitumor effects in cervical cancer, and its combination with bortezomib further enhances this inhibitory effect, probably through maximal activation of p53 and inhibition of BCL-2, suggesting a potential application of APG-115 in the treatment of cervical cancer.
    Keywords:  APG-115; apoptosis; bortezomib; cervical cancer; combination; p53
    DOI:  https://doi.org/10.1097/CAD.0000000000001735
  4. BMC Cancer. 2025 Jun 01. 25(1): 978
    Mdm2 targeting via PROteolysis TArgeting Chimeras (PROTAC) is efficient in p53 wildtype, p53-mutated, and abemaciclib-resistant estrogen receptor-positive cell lines and superior to mdm2 inhibition.
    Alina Goerg, Gerhard Piendl, Veruschka Albert, Olaf Ortmann, Anja Kathrin Wege, Gero Brockhoff.
      
    Keywords:  Abemaciclib; Estrogen receptor-positive breast cancer; Luminal breast cancer; PROTAC; mdm2; p53 mutation
    DOI:  https://doi.org/10.1186/s12885-025-14361-z
  5. Future Oncol. 2025 Jun 04. 1-11
    Real-world survival outcomes and MDM2 prevalence in US patients with metastatic dedifferentiated liposarcoma.
    Steven Robinson, Alyssa B Klein, Stephen A Stanhope, Kathryn Evans, Mark Agulnik.
       BACKGROUND: Limited data exist regarding dedifferentiated liposarcoma (DDLPS) treatment, biomarker frequency, and clinical outcomes. Additional epidemiological data are needed to inform clinical trial design for testing novel therapeutics.
    MATERIALS AND METHODS: Retrospective data from a US-based deidentified clinico-genomic database were analyzed for patients treated for metastatic DDLPS between 2011 and 2021.
    RESULTS: Overall survival (OS), real-world progression-free survival (rwPFS), and time to next treatment (TTNT) were described in the overall cohort (n = 51) and in a subgroup of patients with murine double minute 2 (MDM2) amplification and wild-type tumor protein p53 (TP53 WT) (n = 38, 74.5%). Patients had a median age of 64.8 years, and 62.7% were male. The most common first-line treatment was doxorubicin with olaratumab (23.5%). From time of first-line (1 L) treatment, median OS for the entire cohort and MDM2-amplified, TP53 WT subgroup was 12.6 and 11.7 months, respectively; median rwPFS was 2.5 months for both. Median TTNT was 3.9 months for the full cohort and 4.8 months for the MDM2-amplified, TP53 WT subgroup.
    CONCLUSIONS: The descriptive analysis here contributes real-world data describing treatment patterns, biomarker status, and clinical outcomes for patients with DDLPS, an aggressive and poorly characterized form of LPS with limited treatment options.
    Keywords:  MDM2; Metastatic dedifferentiated liposarcoma; TP53; real-world; survival; treatment patterns
    DOI:  https://doi.org/10.1080/14796694.2025.2502319
  6. Discov Oncol. 2025 Jun 02. 16(1): 983
    Penicilazaphilone C triggers ferroptosis in triple-negative breast cancer cells via the MDM2/p53/SLC7 A11/GPX4 pathway.
    Hua-Tao Liang, Feng-Ying Huang, Wei-Jing Xie, Ming-Hui Chen, Ri-Hong Wu, Shu-Zhen Dai, Wen-Tian Xu, Wu-Ping Zheng, Guang-Hong Tan.
      Penicilazaphilone C (PAC) is a novel azaphilone isolated by our research team. While known for its antitumor properties, the potential of PAC to trigger ferroptosis in triple-negative breast cancer (TNBC) cells remains unexplored. This study aims to assess the ferroptotic induction capability of PAC and elucidate the underlying molecular mechanisms. Our results showed that treatment with PAC demonstrated a dose- and time-dependent inhibition of growth in MDA-MB-231 and MDA-MB-436 cells. Flow cytometry analysis and lactate dehydrogenase assay revealed various forms of cell death induced by PAC in both cell lines. Specifically, flow cytometry analyzed 7-AAD-stained dead cells, and ferroptosis markers, such as lipid peroxidation BODIPY-C11 and Fe2+ ions, identified ferroptosis as the major type of cell death pathway induced by PAC. Moreover, co-administration of the ferroptosis inhibitor Fer-1 notably mitigated PAC-induced cell death, further highlighting ferroptosis as the primary mechanism through which PAC inhibits TNBC cell growth and proliferation. Further exploration of the molecular mechanisms unveiled that PAC modulated the expression of Mouse double minute 2 (MDM2), p53, SLC7A11, and GPX4. In vivo experiments using nude mouse models implanted with MDA-MB-231 and MDA-MB-436 cells demonstrated that PAC treatment effectively suppressed tumor growth, increased levels of BODIPY-C11 and Fe2+ ions in isolated single tumor cells, downregulated MDM2 expression, and upregulated p53, SLC7A11, and GPX4 expression. These results suggest that PAC hinders TNBC cell growth and proliferation by modulating the MDM2/p53/SLC7A11/GPX4 axis to induce ferroptosis, positioning PAC as a promising azaphilone candidate for TNBC therapy.
    Keywords:  Azaphilone compound; E3 ubiquitin ligase MDM2; Ferroptosis; Penicilazaphilone C; Triple-negative breast cancer
    DOI:  https://doi.org/10.1007/s12672-025-02687-w
  7. Adv Sci (Weinh). 2025 Jun 05. e03473
    Lipid Droplet-Organized MDM2-Mediated P53 Degradation: A Metabolic Switch Governing Diet-Driven Tumor Progression.
    Haiyang Liu, Lin Jing, Yixin Li, Jinxing Zhou, Xiaohui Cui, Sen Li, Shijie Yang, Fangming Kan, Junfeng Du, Wentao Zhong, Sheng Yu, Ning Wang, Xing Jia, Junhui Li, Pan Nie, Zhenzhong Chen, Ying Han, Lingxi Jiang, Xiyun Yan, Hongxia Duan, Baiyong Shen.
      TP53 inactivation in human cancers often results from MDM2/MDMX overexpression, yet therapeutic targeting remains challenging owing to incomplete mechanistic understanding. Lipid droplet (LD) enrichment is identified as a key trigger for MDM2-mediated p53 degradation. High-fat diet (HFD)-induced LD accumulation in tumor cells elevates LD-surface MDM2 through Cyb5r3-Myh9 interactions, which recruit cytoplasmic p53/Myh9 complexes to LDs. This spatial proximity enhances MDM2-p53 binding, accelerating its ubiquitination and proteasomal degradation. Degraded p53 releases the RPS3A-C/EBPβ complex, upregulating LD-promoting factors such as CD36 to establish a cell-autonomous feed-forward loop. Critically, pharmacological LD reduction (via lipogenesis inhibitors) or switching of tumor-bearing mice from an HFD to a normal diet restores p53 levels and suppresses tumor growth. These findings delineate a lipid-driven regulatory axis in which LD biogenesis initiates MDM2-dependent p53 destruction, reshaping tumor cell lipid metabolism. This mechanism links dietary lipids to oncogenesis through organelle-specific protein trafficking and provides a therapeutic rationale for targeting lipid metabolism in tumors. This study resolves critical gaps in p53 regulation while proposing dual intervention strategies: disrupting LD-MDM2 colocalization and modulating lipid availability.
    Keywords:  high‐fat diets; lipid droplets; p53 degradation initiation; tumor growth
    DOI:  https://doi.org/10.1002/advs.202503473
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