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Peer-reviewedCC BYCell death & disease

Targeted degradation of P-TEFb via MDM2 substrate substitution collapses oncogenic transcriptional programs in MDM2-amplified cancers.

  • Ye Chen1,2
  • Long Xie3,4
  • Xian Guan5
  • Xingze Huang4
  • Jiangyu Liu3
  • Zhipeng Zhu4
  • Yuanfang Wu3
  • Hanjun Guo3,4
  • Lin Ma5
  • Ying Zhang4
  • Jiawei Zhou3
  • Suya Zheng3
3 more authors
  • Ruhong Zhou6,7,8,9
  • Xin Han10,11
  • Liang Xu12,13,14,15
15 affiliations
  1. 1Department of Surgical Oncology, and Pediatric Cancer Research Center, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Children and Adolescents' Health and Diseases, Hangzhou, China. [email protected].
  2. 2Cancer Center, Zhejiang University, Hangzhou, China. [email protected].
  3. 3Department of Surgical Oncology, and Pediatric Cancer Research Center, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Children and Adolescents' Health and Diseases, Hangzhou, China.
  4. 4Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou, China.
  5. 5Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education) of the Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
  6. 6Cancer Center, Zhejiang University, Hangzhou, China. [email protected].
  7. 7Institute of Biophysics, College of Life Sciences, Zhejiang University, Hangzhou, China. [email protected].
  8. 8Shanghai Institute for Advanced Study, Zhejiang University, Shanghai, China. [email protected].
  9. 9Institute of Quantitative Biology, Zhejiang University, Hangzhou, China. [email protected].
  10. 10Cancer Center, Zhejiang University, Hangzhou, China. [email protected].
  11. 11Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education) of the Second Affiliated Hospital and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  12. 12Department of Surgical Oncology, and Pediatric Cancer Research Center, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Children and Adolescents' Health and Diseases, Hangzhou, China. [email protected].
  13. 13Cancer Center, Zhejiang University, Hangzhou, China. [email protected].
  14. 14Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou, China. [email protected].
  15. 15Department of Radiation Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
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Abstract

MDM2 is an oncogenic E3 ubiquitin ligase best known for targeting the tumor suppressor p53 and is frequently amplified in human cancers, including dedifferentiated liposarcoma (DDLPS). We show that supraphysiological MDM2 expression can be exploited to reprogram its ligase activity toward selective degradation of oncogenic transcriptional machinery. Using a substrate substitution strategy, we developed an MDM2-recruiting degrader dCDK9-010 that targets positive transcription elongation factor b, inducing its proteasomal degradation while simultaneously stabilizing p53. This dual action disrupts RNA polymerase II abundance and elongation, preferentially impairing enhancer-driven transcriptional programs that sustain tumor growth. In DDLPS models, this approach produces potent antitumor activity with favorable pharmacokinetic and safety profiles, triggers apoptosis, and enhances macrophage-mediated tumor cell clearance. These findings establish substrate substitution-based reprogramming of MDM2 as a generalizable targeted protein degradation strategy and identify MDM2 amplification as a predictive biomarker for therapeutic response across cancer types, with particular relevance to liposarcoma.

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Cite

BibTeXRIS
BibTeX
@article{chen2026targeted,
  title = {{Targeted degradation of P-TEFb via MDM2 substrate substitution collapses oncogenic transcriptional programs in MDM2-amplified cancers.}},
  author = {Ye Chen and Long Xie and Xian Guan and Xingze Huang and Jiangyu Liu and Zhipeng Zhu and Yuanfang Wu and Hanjun Guo and Lin Ma and Ying Zhang and Jiawei Zhou and Suya Zheng and Ruhong Zhou and Xin Han and Liang Xu},
  journal = {Cell death \& disease},
  year = {2026},
  month = aug,
  doi = {10.1038/s41419-026-09134-w},
  url = {https://europepmc.org/article/MED/42957651},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Targeted degradation of P-TEFb via MDM2 substrate substitution collapses oncogenic transcriptional programs in MDM2-amplified cancers.
AU  - Ye Chen
AU  - Long Xie
AU  - Xian Guan
AU  - Xingze Huang
AU  - Jiangyu Liu
AU  - Zhipeng Zhu
AU  - Yuanfang Wu
AU  - Hanjun Guo
AU  - Lin Ma
AU  - Ying Zhang
AU  - Jiawei Zhou
AU  - Suya Zheng
AU  - Ruhong Zhou
AU  - Xin Han
AU  - Liang Xu
PY  - 2026
DA  - 2026/08/01
JO  - Cell death & disease
DO  - 10.1038/s41419-026-09134-w
UR  - https://europepmc.org/article/MED/42957651
AB  - MDM2 is an oncogenic E3 ubiquitin ligase best known for targeting the tumor suppressor p53 and is frequently amplified in human cancers, including dedifferentiated liposarcoma (DDLPS). We show that supraphysiological MDM2 expression can be exploited to reprogram its ligase activity toward selective degradation of oncogenic transcriptional machinery. Using a substrate substitution strategy, we developed an MDM2-recruiting degrader dCDK9-010 that targets positive transcription elongation factor b, inducing its proteasomal degradation while simultaneously stabilizing p53. This dual action disrupts RNA polymerase II abundance and elongation, preferentially impairing enhancer-driven transcriptional programs that sustain tumor growth. In DDLPS models, this approach produces potent antitumor activity with favorable pharmacokinetic and safety profiles, triggers apoptosis, and enhances macrophage-mediated tumor cell clearance. These findings establish substrate substitution-based reprogramming of MDM2 as a generalizable targeted protein degradation strategy and identify MDM2 amplification as a predictive biomarker for therapeutic response across cancer types, with particular relevance to liposarcoma.
SN  - 2041-4889
ER  -