Efficacy analysis of targeted P53 therapy in solid tumors

Friedman PN, Chen X, Bargonetti J, Prives C. The p53 protein is an unusually shaped tetramer that binds directly to DNA. Proc Natl Acad Sci U S A. 1993;90:3319–23.

CAS  PubMed  PubMed Central  Google Scholar 

Joerger AC, Fersht AR. The tumor suppressor p53: from structures to drug discovery. Cold Spring Harb Perspect Biol. 2010;2: a000919.

PubMed  PubMed Central  Google Scholar 

Kastenhuber ER, Lowe SW. Putting p53 in context. Cell. 2017;170:1062–78.

CAS  PubMed  PubMed Central  Google Scholar 

Levine AJ. p53: 800 million years of evolution and 40 years of discovery. Nat Rev Cancer. 2020;20:471–80.

CAS  PubMed  Google Scholar 

Ding Y, Xue H, Ding X, Zhao Y, Zhao Z, Wang D, et al. On the complexity measures of mutation hotspots in human P53 protein. Chaos. 2020;30: 073118.

CAS  PubMed  Google Scholar 

Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harb Perspect Biol. 2010;2: a001008.

PubMed  PubMed Central  Google Scholar 

Baker SJ, Fearon ER, Nigro JM, Hamilton SR, Preisinger AC, Jessup JM, et al. Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science. 1989;244:217–21.

CAS  PubMed  Google Scholar 

Takahashi T, Nau MM, Chiba I, Birrer MJ, Rosenberg RK, Vinocour M, et al. p53: a frequent target for genetic abnormalities in lung cancer. Science. 1989;246:491–4.

CAS  PubMed  Google Scholar 

Varley JM, Brammar WJ, Lane DP, Swallow JE, Dolan C, Walker RA. Loss of chromosome 17p13 sequences and mutation of p53 in human breast carcinomas. Oncogene. 1991;6:413–21.

CAS  PubMed  Google Scholar 

Kaelbling M, Burk RD, Atkin NB, Johnson AB, Klinger HP. Loss of heterozygosity on chromosome 17p and mutant p53 in HPV-negative cervical carcinomas. Lancet Lond Engl. 1992;340:140–2.

CAS  Google Scholar 

Donehower LA, Soussi T, Korkut A, Liu Y, Schultz A, Cardenas M, et al. Integrated analysis of TP53 gene and pathway alterations in the cancer genome atlas. Cell Rep. 2019;28:1370-1384.e5.

CAS  PubMed  PubMed Central  Google Scholar 

Brosh R, Rotter V. When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer. 2009;9:701–13.

CAS  PubMed  Google Scholar 

Stein Y, Aloni-Grinstein R, Rotter V. Mutant p53 oncogenicity: dominant-negative or gain-of-function? Carcinogenesis. 2020;41:1635–47.

CAS  PubMed  Google Scholar 

Olotu FA, Soliman MES. From mutational inactivation to aberrant gain-of-function: unraveling the structural basis of mutant p53 oncogenic transition. J Cell Biochem. 2018;119:2646–52.

CAS  PubMed  Google Scholar 

Martins CP, Brown-Swigart L, Evan GI. Modeling the therapeutic efficacy of p53 restoration in tumors. Cell. 2006;127:1323–34.

CAS  PubMed  Google Scholar 

Mora P, Carbajo RJ, Pineda-Lucena A, Sánchez del Pino MM, Pérez-Payá E. Solvent-exposed residues located in the beta-sheet modulate the stability of the tetramerization domain of p53–a structural and combinatorial approach. Proteins. 2008;71:1670–85.

CAS  PubMed  Google Scholar 

Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature. 1997;387:296–9.

CAS  PubMed  Google Scholar 

Tournillon A-S, López I, Malbert-Colas L, Findakly S, Naski N, Olivares-Illana V, et al. p53 binds the mdmx mRNA and controls its translation. Oncogene. 2017;36:723–30.

CAS  PubMed  Google Scholar 

Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000;408:307–10.

CAS  PubMed  Google Scholar 

Zheng J, Miao F, Wang Z, Ma Y, Lin Z, Chen Y, et al. Identification of MDM2 as a prognostic and immunotherapeutic biomarker in a comprehensive pan-cancer analysis: a promising target for breast cancer, bladder cancer and ovarian cancer immunotherapy. Life Sci. 2023;327: 121832.

CAS  PubMed  Google Scholar 

Klein AM, de Queiroz RM, Venkatesh D, Prives C. The roles and regulation of MDM2 and MDMX: it is not just about p53. Genes Dev. 2021;35:575–601.

CAS  PubMed  PubMed Central  Google Scholar 

Wurz RP, Cee VJ. Targeted degradation of MDM2 as a new approach to improve the efficacy of MDM2-p53 inhibitors. J Med Chem. 2019;62:445–7.

CAS  PubMed  Google Scholar 

Hines J, Lartigue S, Dong H, Qian Y, Crews CM. MDM2-recruiting PROTAC offers superior, synergistic antiproliferative activity via simultaneous degradation of BRD4 and stabilization of p53. Cancer Res. 2019;79:251–62.

CAS  PubMed  Google Scholar 

Huang J, Fu X, Qiu F, Liang Z, Cao C, Wang Z, et al. Discovery of a natural ent-kaurene diterpenoid oridonin as an E3 ligase recruiter for PROTACs. J Am Chem Soc. 2025;147:1920–37.

CAS  PubMed  Google Scholar 

Fu X, Li J, Chen X, Chen H, Wang Z, Qiu F, et al. Repurposing AS1411 for constructing ANM-PROTACs. Cell Chem Biol. 2024;31:1290-1304.e7.

CAS  PubMed  Google Scholar 

Aguilar A, Yang J, Li Y, McEachern D, Huang L, Razzouk S, et al. Discovery of MD-265: a potent MDM2 degrader that achieves complete tumor regression and improves long-term survival of mice with leukemia. J Med Chem. 2024;67:19503–18.

CAS  PubMed  Google Scholar 

Adams CM, Mitra R, Xiao Y, Michener P, Palazzo J, Chao A, et al. Targeted MDM2 degradation reveals a new vulnerability for p53-inactivated triple-negative breast cancer. Cancer Discov. 2023;13:1210–29.

CAS  PubMed  PubMed Central  Google Scholar 

Concin N, Zeillinger C, Stimpfel M, Schiebel I, Tong D, Wolff U, et al. p53-dependent radioresistance in ovarian carcinoma cell lines. Cancer Lett. 2000;150:191–9.

CAS  PubMed  Google Scholar 

Ingelshed K, Spiegelberg D, Kannan P, Påvénius L, Hacheney J, Jiang L, et al. The MDM2 inhibitor navtemadlin arrests mouse melanoma growth in vivo and potentiates radiotherapy. Cancer Res Commun. 2022;2:1075–88.

CAS  PubMed  PubMed Central  Google Scholar 

Spiegelberg D, Mortensen AC, Lundsten S, Brown CJ, Lane DP, Nestor M. The MDM2/MDMX-p53 antagonist PM2 radiosensitizes wild-type p53 tumors. Cancer Res. 2018;78:5084–93.

CAS  PubMed  Google Scholar 

Stewart-Ornstein J, Iwamoto Y, Miller MA, Prytyskach MA, Ferretti S, Holzer P, et al. p53 dynamics vary between tissues and are linked with radiation sensitivity. Nat Commun. 2021;12:898.

CAS  PubMed  PubMed Central  Google Scholar 

Ji N-N, Li S-N, Shao L, Li Q, Xu J-N, Zeng Y-C. MDMX enhances radiosensitivity in lung adenocarcinoma and squamous cell carcinoma by inhibiting P53-mediated autophagy. Cell Oncol Dordr Neth. 2025.

Leng RP, Lin Y, Ma W, Wu H, Lemmers B, Chung S, et al. Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell. 2003;112:779–91.

CAS  PubMed  Google Scholar 

Dornan D, Wertz I, Shimizu H, Arnott D, Frantz GD, Dowd P, et al. The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature. 2004;429:86–92.

CAS  PubMed  Google Scholar 

Chen D, Kon N, Li M, Zhang W, Qin J, Gu W. ARF-BP1/mule is a critical mediator of the ARF tumor suppressor. Cell. 2005;121:1071–83.

CAS  PubMed  Google Scholar 

Bergamaschi D, Samuels Y, O’Neil NJ, Trigiante G, Crook T, Hsieh J-K, et al. iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human. Nat Genet. 2003;33:162–7.

CAS  PubMed  Google Scholar 

Bulavin DV, Demidov ON, Saito S, Kauraniemi P, Phillips C, Amundson SA, et al. Amplification of PPM1D in human tumors abrogates p53 tumor-suppressor activity. Nat Genet. 2002;31:210–5.

CAS  PubMed  Google Scholar 

Lulla RR, Goldman S, Yamada T, Beattie CW, Bressler L, Pacini M, et al. Phase I trial of p28 (NSC745104), a non-HDM2-mediated peptide inhibitor of p53 ubiquitination in pediatric patients with recurrent or progressive central nervous system tumors: A Pediatric Brain Tumor Consortium Study. Neuro-Oncol. 2016;18:1319–25.

CAS  PubMed  PubMed Central 

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