Prostate cancer remains a leading cause of cancer-related mortality in men, with advanced stages posing significant treatment challenges due to high morbidity and mortality. Among genetic alterations, TP53 mutations are among the most prevalent in cancers and are strongly associated with poor clinical outcomes and therapeutic resistance. This review investigates the role of TP53 mutations in prostate cancer progression, prognosis, and therapeutic development. A comprehensive analysis of preclinical and clinical studies was conducted to elucidate the molecular mechanisms, clinical implications, and potential therapeutic approaches associated with TP53 alterations in prostate cancer. TP53 mutations are highly prevalent in advanced stages, contributing to genomic instability, aggressive tumor phenotypes, and resistance to standard treatments. Emerging evidence supports the utility of liquid biopsy techniques, such as circulating tumor DNA analysis, for detecting TP53 mutations, providing prognostic value and facilitating early intervention strategies. Novel therapeutic approaches targeting TP53 have shown promise in preclinical settings, but their clinical efficacy requires further validation. Overall, TP53 mutations represent a critical biomarker for disease progression and therapeutic response in prostate cancer. Advances in detection methods and targeted therapies hold significant potential to improve outcomes for patients with TP53-mutated prostate cancer. Further research is essential to integrate TP53-based strategies into routine clinical practice.

Department of Urology 2nd Faculty of Medicine Charles University 150 06 Prague Czech Republic

Department of Urology Medical University of Vienna 1090 Vienna Austria

Department of Urology University of Texas Southwestern Medical Center Dallas TX 75390 USA

Department of Urology Weill Cornell Medical College New York NY 10065 USA

Hourani Center for Applied Scientific Research Al Ahliyya Amman University Amman 19328 Jordan

Karl Landsteiner Institute of Urology and Andrology 1090 Vienna Austria

Zobrazit více v PubMed

Withrow D., Pilleron S., Nikita N., Ferlay J., Sharma S., Nicholson B., Rebbeck T.R., Lu-Yao G. Current and projected number of years of life lost due to prostate cancer: A global study. Prostate. 2022;82:1088–1097. doi: 10.1002/pros.24360. PubMed DOI PMC

Van den Broeck T., van den Bergh R.C.N., Arfi N., Gross T., Moris L., Briers E., Cumberbatch M., De Santis M., Tilki D., Fanti S., et al. Prognostic Value of Biochemical Recurrence Following Treatment with Curative Intent for Prostate Cancer: A Systematic Review. Eur. Urol. 2019;75:967–987. doi: 10.1016/j.eururo.2018.10.011. PubMed DOI

Tilki D., van den Bergh R.C.N., Briers E., Van den Broeck T., Brunckhorst O., Darraugh J., Eberli D., De Meerleer G., De Santis M., Farolfi A., et al. EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer. Part II-2024 Update: Treatment of Relapsing and Metastatic Prostate Cancer. Eur. Urol. 2024;86:164–182. doi: 10.1016/j.eururo.2024.04.010. PubMed DOI

de Bono J., Mateo J., Fizazi K., Saad F., Shore N., Sandhu S., Chi K.N., Sartor O., Agarwal N., Olmos D., et al. Olaparib for Metastatic Castration-Resistant Prostate Cancer. N. Engl. J. Med. 2020;382:2091–2102. doi: 10.1056/NEJMoa1911440. PubMed DOI

Fizazi K., Piulats J.M., Reaume M.N., Ostler P., McDermott R., Gingerich J.R., Pintus E., Sridhar S.S., Bambury R.M., Emmenegger U., et al. Rucaparib or Physician’s Choice in Metastatic Prostate Cancer. N. Engl. J. Med. 2023;388:719–732. doi: 10.1056/NEJMoa2214676. PubMed DOI PMC

Agarwal N., Azad A.A., Carles J., Fay A.P., Matsubara N., Heinrich D., Szczylik C., De Giorgi U., Young Joung J., Fong P.C.C., et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): A randomised, placebo-controlled, phase 3 trial. Lancet. 2023;402:291–303. doi: 10.1016/S0140-6736(23)01055-3. PubMed DOI

Robinson D., Van Allen E.M., Wu Y.M., Schultz N., Lonigro R.J., Mosquera J.M., Montgomery B., Taplin M.E., Pritchard C.C., Attard G., et al. Integrative Clinical Genomics of Advanced Prostate Cancer. Cell. 2015;162:454. doi: 10.1016/j.cell.2015.06.053. PubMed DOI

Abida W., Cyrta J., Heller G., Prandi D., Armenia J., Coleman I., Cieslik M., Benelli M., Robinson D., Van Allen E.M., et al. Genomic correlates of clinical outcome in advanced prostate cancer. Proc. Natl. Acad. Sci. USA. 2019;116:11428–11436. doi: 10.1073/pnas.1902651116. PubMed DOI PMC

Nguyen B., Mota J.M., Nandakumar S., Stopsack K.H., Weg E., Rathkopf D., Morris M.J., Scher H.I., Kantoff P.W., Gopalan A., et al. Pan-cancer Analysis of CDK12 Alterations Identifies a Subset of Prostate Cancers with Distinct Genomic and Clinical Characteristics. Eur. Urol. 2020;78:671–679. doi: 10.1016/j.eururo.2020.03.024. PubMed DOI PMC

Shi W., Wang Y., Zhao Y., Kim J.J., Li H., Meng C., Chen F., Zhang J., Mak D.H., Van V., et al. Immune checkpoint B7-H3 is a therapeutic vulnerability in prostate cancer harboring PTEN and TP53 deficiencies. Sci. Transl. Med. 2023;15:eadf6724. doi: 10.1126/scitranslmed.adf6724. PubMed DOI PMC

Tsujino T., Takai T., Hinohara K., Gui F., Tsutsumi T., Bai X., Miao C., Feng C., Gui B., Sztupinszki Z., et al. CRISPR screens reveal genetic determinants of PARP inhibitor sensitivity and resistance in prostate cancer. Nat. Commun. 2023;14:252. doi: 10.1038/s41467-023-35880-y. PubMed DOI PMC

Donehower L.A., Soussi T., Korkut A., Liu Y., Schultz A., Cardenas M., Li X., Babur O., Hsu T.K., Lichtarge O., et al. Integrated Analysis of TP53 Gene and Pathway Alterations in The Cancer Genome Atlas. Cell Rep. 2019;28:3010. doi: 10.1016/j.celrep.2019.08.061. PubMed DOI

Cordon-Cardo C., Latres E., Drobnjak M., Oliva M.R., Pollack D., Woodruff J.M., Marechal V., Chen J., Brennan M.F., Levine A.J. Molecular abnormalities of mdm2 and p53 genes in adult soft tissue sarcomas. Cancer Res. 1994;54:794–799. PubMed

Lang G.A., Iwakuma T., Suh Y.A., Liu G., Rao V.A., Parant J.M., Valentin-Vega Y.A., Terzian T., Caldwell L.C., Strong L.C., et al. Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell. 2004;119:861–872. doi: 10.1016/j.cell.2004.11.006. PubMed DOI

Cooks T., Pateras I.S., Tarcic O., Solomon H., Schetter A.J., Wilder S., Lozano G., Pikarsky E., Forshew T., Rosenfeld N., et al. Mutant p53 prolongs NF-κB activation and promotes chronic inflammation and inflammation-associated colorectal cancer. Cancer Cell. 2013;23:634–646. doi: 10.1016/j.ccr.2013.03.022. PubMed DOI PMC

Gudkov A.V., Komarova E.A. The role of p53 in determining sensitivity to radiotherapy. Nat. Rev. Cancer. 2003;3:117–129. doi: 10.1038/nrc992. PubMed DOI

Anbalagan S., Ström C., Downs J.A., Jeggo P.A., McBay D., Wilkins A., Rothkamm K., Harrington K.J., Yarnold J.R., Somaiah N. TP53 modulates radiotherapy fraction size sensitivity in normal and malignant cells. Sci. Rep. 2021;11:7119. doi: 10.1038/s41598-021-86681-6. PubMed DOI PMC

Purvis J.E., Karhohs K.W., Mock C., Batchelor E., Loewer A., Lahav G. p53 dynamics control cell fate. Science. 2012;336:1440–1444. doi: 10.1126/science.1218351. PubMed DOI PMC

Donehower L.A., Harvey M., Slagle B.L., McArthur M.J., Montgomery C.A., Butel J.S., Bradley A. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992;356:215–221. doi: 10.1038/356215a0. PubMed DOI

Chen Z., Trotman L.C., Shaffer D., Lin H.K., Dotan Z.A., Niki M., Koutcher J.A., Scher H.I., Ludwig T., Gerald W., et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature. 2005;436:725–730. doi: 10.1038/nature03918. PubMed DOI PMC

Bougeard G., Renaux-Petel M., Flaman J.M., Charbonnier C., Fermey P., Belotti M., Gauthier-Villars M., Stoppa-Lyonnet D., Consolino E., Brugières L., et al. Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. J. Clin. Oncol. 2015;33:2345–2352. doi: 10.1200/JCO.2014.59.5728. PubMed DOI

Bouaoun L., Sonkin D., Ardin M., Hollstein M., Byrnes G., Zavadil J., Olivier M. TP53 Variations in Human Cancers: New Lessons from the IARC TP53 Database and Genomics Data. Hum. Mutat. 2016;37:865–876. doi: 10.1002/humu.23035. PubMed DOI

Ding D., Blee A.M., Zhang J., Pan Y., Becker N.A., Maher L.J., Jimenez R., Wang L., Huang H. Gain-of-function mutant p53 together with ERG proto-oncogene drive prostate cancer by beta-catenin activation and pyrimidine synthesis. Nat. Commun. 2023;14:4671. doi: 10.1038/s41467-023-40352-4. PubMed DOI PMC

Peuget S., Zhou X., Selivanova G. Translating p53-based therapies for cancer into the clinic. Nat. Rev. Cancer. 2024;24:192–215. doi: 10.1038/s41568-023-00658-3. PubMed DOI

Wang B., Niu D., Lai L., Ren E.C. p53 increases MHC class I expression by upregulating the endoplasmic reticulum aminopeptidase ERAP1. Nat. Commun. 2013;4:2359. doi: 10.1038/ncomms3359. PubMed DOI PMC

Ho J.N.H.G., Schmidt D., Lowinus T., Ryoo J., Dopfer E.P., Gonzalo Núñez N., Costa-Pereira S., Toffalori C., Punta M., Fetsch V., et al. Targeting MDM2 enhances antileukemia immunity after allogeneic transplantation via MHC-II and TRAIL-R1/2 upregulation. Blood. 2022;140:1167–1181. doi: 10.1182/blood.2022016082. PubMed DOI PMC

Cortez M.A., Ivan C., Valdecanas D., Wang X., Peltier H.J., Ye Y., Araujo L., Carbone D.P., Shilo K., Giri D.K., et al. PDL1 Regulation by p53 via miR-34. J. Natl. Cancer Inst. 2016;108:djv303. doi: 10.1093/jnci/djv303. PubMed DOI PMC

Langenbach M., Giesler S., Richtsfeld S., Costa-Pereira S., Rindlisbacher L., Wertheimer T., Braun L.M., Andrieux G., Duquesne S., Pfeifer D., et al. MDM2 Inhibition Enhances Immune Checkpoint Inhibitor Efficacy by Increasing IL15 and MHC Class II Production. Mol. Cancer Res. 2023;21:849–864. doi: 10.1158/1541-7786.MCR-22-0898. PubMed DOI PMC

Textor S., Fiegler N., Arnold A., Porgador A., Hofmann T.G., Cerwenka A. Human NK cells are alerted to induction of p53 in cancer cells by upregulation of the NKG2D ligands ULBP1 and ULBP2. Cancer Res. 2011;71:5998–6009. doi: 10.1158/0008-5472.CAN-10-3211. PubMed DOI

Izquierdo E., Vorholt D., Blakemore S., Sackey B., Nolte J.L., Barbarino V., Schmitz J., Nickel N., Bachurski D., Lobastova L., et al. Extracellular vesicles and PD-L1 suppress macrophages, inducing therapy resistance in TP53-deficient B-cell malignancies. Blood. 2022;139:3617–3629. doi: 10.1182/blood.2021014007. PubMed DOI

Pan R., Ryan J., Pan D., Wucherpfennig K.W., Letai A. Augmenting NK cell-based immunotherapy by targeting mitochondrial apoptosis. Cell. 2022;185:1521–1538.e1518. doi: 10.1016/j.cell.2022.03.030. PubMed DOI PMC

Cooks T., Pateras I.S., Jenkins L.M., Patel K.M., Robles A.I., Morris J., Forshew T., Appella E., Gorgoulis V.G., Harris C.C. Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246. Nat. Commun. 2018;9:771. doi: 10.1038/s41467-018-03224-w. PubMed DOI PMC

Yang P., Li Q.J., Feng Y., Zhang Y., Markowitz G.J., Ning S., Deng Y., Zhao J., Jiang S., Yuan Y., et al. TGF-β-miR-34a-CCL22 signaling-induced Treg cell recruitment promotes venous metastases of HBV-positive hepatocellular carcinoma. Cancer Cell. 2012;22:291–303. doi: 10.1016/j.ccr.2012.07.023. PubMed DOI PMC

Markowski M.C., Wang H., De Marzo A.M., Schweizer M.T., Antonarakis E.S., Denmeade S.R. Clinical Efficacy of Bipolar Androgen Therapy in Men with Metastatic Castration-Resistant Prostate Cancer and Combined Tumor-Suppressor Loss. Eur. Urol. Open Sci. 2022;41:112–115. doi: 10.1016/j.euros.2022.05.006. PubMed DOI PMC

Markowski M.C., Kachhap S., De Marzo A.M., Sena L.A., Luo J., Denmeade S.R., Antonarakis E.S. Molecular and Clinical Characterization of Patients with Metastatic Castration Resistant Prostate Cancer Achieving Deep Responses to Bipolar Androgen Therapy. Clin. Genitourin. Cancer. 2022;20:97–101. doi: 10.1016/j.clgc.2021.08.001. PubMed DOI PMC

Chopra H., Khan Z., Contreras J., Wang H., Sedrak A., Zhu Y. Activation of p53 and destabilization of androgen receptor by combinatorial inhibition of MDM2 and MDMX in prostate cancer cells. Oncotarget. 2018;9:6270–6281. doi: 10.18632/oncotarget.23569. PubMed DOI PMC

Lei K., Sun R., Chen L.H., Diplas B.H., Moure C.J., Wang W., Hansen L.J., Tao Y., Chen X., Chen C.J., et al. Mutant allele quantification reveals a genetic basis for TP53 mutation-driven castration resistance in prostate cancer cells. Sci. Rep. 2018;8:12507. doi: 10.1038/s41598-018-30062-z. PubMed DOI PMC

Fan Y., Fan H., Quan Z., Wu X. Ionizing Radiation Combined with PARP1 Inhibitor Reduces Radioresistance in Prostate Cancer with RB1/TP53 Loss. Cancer Investig. 2021;39:423–434. doi: 10.1080/07357907.2021.1899200. PubMed DOI

Blee A.M., He Y., Yang Y., Ye Z., Yan Y., Pan Y., Ma T., Dugdale J., Kuehn E., Kohli M., et al. Controls Luminal Epithelial Lineage and Antiandrogen Sensitivity in. Clin. Cancer Res. 2018;24:4551–4565. doi: 10.1158/1078-0432.CCR-18-0653. PubMed DOI PMC

McCann J.J., Vasilevskaya I.A., McNair C., Gallagher P., Neupane N.P., de Leeuw R., Shafi A.A., Dylgjeri E., Mandigo A.C., Schiewer M.J., et al. Mutant p53 elicits context-dependent pro-tumorigenic phenotypes. Oncogene. 2022;41:444–458. doi: 10.1038/s41388-021-01903-5. PubMed DOI PMC

Moretti R.M., Montagnani Marelli M., Taylor D.M., Martini P.G., Marzagalli M., Limonta P. Gonadotropin-releasing hormone agonists sensitize, and resensitize, prostate cancer cells to docetaxel in a p53-dependent manner. PLoS ONE. 2014;9:e93713. doi: 10.1371/journal.pone.0093713. PubMed DOI PMC

Yamada Y., Beltran H. Clinical and Biological Features of Neuroendocrine Prostate Cancer. Curr. Oncol. Rep. 2021;23:15. doi: 10.1007/s11912-020-01003-9. PubMed DOI PMC

Mu P., Zhang Z., Benelli M., Karthaus W.R., Hoover E., Chen C.C., Wongvipat J., Ku S.Y., Gao D., Cao Z., et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science. 2017;355:84–88. doi: 10.1126/science.aah4307. PubMed DOI PMC

Bezzi M., Seitzer N., Ishikawa T., Reschke M., Chen M., Wang G., Mitchell C., Ng C., Katon J., Lunardi A., et al. Diverse genetic-driven immune landscapes dictate tumor progression through distinct mechanisms. Nat. Med. 2018;24:165–175. doi: 10.1038/nm.4463. PubMed DOI

Xie H., Li C., Dang Q., Chang L.S., Li L. Infiltrating mast cells increase prostate cancer chemotherapy and radiotherapy resistances via modulation of p38/p53/p21 and ATM signals. Oncotarget. 2016;7:1341–1353. doi: 10.18632/oncotarget.6372. PubMed DOI PMC

Velho P.I., Lim D., Wang H., Park J.C., Kaur H.B., Almutairi F., Carducci M.A., Denmeade S.R., Markowski M.C., Isaacs W.B., et al. Molecular Characterization and Clinical Outcomes of Primary Gleason Pattern 5 Prostate Cancer After Radical Prostatectomy. JCO Precis. Oncol. 2019;3:1–3. doi: 10.1200/PO.19.00081. PubMed DOI PMC

Mateo J., Seed G., Bertan C., Rescigno P., Dolling D., Figueiredo I., Miranda S., Nava Rodrigues D., Gurel B., Clarke M., et al. Genomics of lethal prostate cancer at diagnosis and castration resistance. J. Clin. Investig. 2020;130:1743–1751. doi: 10.1172/JCI132031. PubMed DOI PMC

Nientiedt C., Budczies J., Endris V., Kirchner M., Schwab C., Jurcic C., Behnisch R., Hoveida S., Lantwin P., Kaczorowski A., et al. Mutations in TP53 or DNA damage repair genes define poor prognostic subgroups in primary prostate cancer. Urol. Oncol. 2022;40:8.e11–18.e18. doi: 10.1016/j.urolonc.2021.06.024. PubMed DOI

Fu M., Wang Q., Wang H., Dai Y., Wang J., Kang W., Cui Z., Jin X. Immune-Related Genes Are Prognostic Markers for Prostate Cancer Recurrence. Front. Genet. 2021;12:639642. doi: 10.3389/fgene.2021.639642. PubMed DOI PMC

Abida W., Armenia J., Gopalan A., Brennan R., Walsh M., Barron D., Danila D., Rathkopf D., Morris M., Slovin S., et al. Prospective Genomic Profiling of Prostate Cancer Across Disease States Reveals Germline and Somatic Alterations That May Affect Clinical Decision Making. JCO Precis. Oncol. 2017;2017:1–16. doi: 10.1200/PO.17.00029. PubMed DOI PMC

Hong M.K., Macintyre G., Wedge D.C., Van Loo P., Patel K., Lunke S., Alexandrov L.B., Sloggett C., Cmero M., Marass F., et al. Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer. Nat. Commun. 2015;6:6605. doi: 10.1038/ncomms7605. PubMed DOI PMC

Hamid A.A., Gray K.P., Shaw G., MacConaill L.E., Evan C., Bernard B., Loda M., Corcoran N.M., Van Allen E.M., Choudhury A.D., et al. Compound Genomic Alterations of TP53, PTEN, and RB1 Tumor Suppressors in Localized and Metastatic Prostate Cancer. Eur. Urol. 2019;76:89–97. doi: 10.1016/j.eururo.2018.11.045. PubMed DOI

Zhou J., Lai Y., Peng S., Tang C., Chen Y., Li L., Huang H., Guo Z. Comprehensive analysis of TP53 and SPOP mutations and their impact on survival in metastatic prostate cancer. Front. Oncol. 2022;12:957404. doi: 10.3389/fonc.2022.957404. PubMed DOI PMC

Gilson C., Ingleby F., Gilbert D.C., Parry M.A., Atako N.B., Ali A., Hoyle A., Clarke N.W., Gannon M., Wanstall C., et al. Genomic Profiles of De Novo High- and Low-Volume Metastatic Prostate Cancer: Results From a 2-Stage Feasibility and Prevalence Study in the STAMPEDE Trial. JCO Precis. Oncol. 2020;4:882–897. doi: 10.1200/PO.19.00388. PubMed DOI

Cussenot O., Timms K.M., Perrot E., Blanchet P., Brureau L., Solimeno C., Fromont G., Comperat E., Cancel-Tassin G. Tumour-based Mutational Profiles Predict Visceral Metastasis Outcome and Early Death in Prostate Cancer Patients. Eur. Urol. Oncol. 2024;7:597–604. doi: 10.1016/j.euo.2023.12.003. PubMed DOI

Velez M.G., Kosiorek H.E., Egan J.B., McNatty A.L., Riaz I.B., Hwang S.R., Stewart G.A., Ho T.H., Moore C.N., Singh P., et al. Differential impact of tumor suppressor gene (TP53, PTEN, RB1) alterations and treatment outcomes in metastatic, hormone-sensitive prostate cancer. Prostate Cancer Prostatic Dis. 2022;25:479–483. doi: 10.1038/s41391-021-00430-4. PubMed DOI PMC

Maughan B.L., Guedes L.B., Boucher K., Rajoria G., Liu Z., Klimek S., Zoino R., Antonarakis E.S., Lotan T.L. p53 status in the primary tumor predicts efficacy of subsequent abiraterone and enzalutamide in castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. 2018;21:260–268. doi: 10.1038/s41391-017-0027-4. PubMed DOI

De Laere B., Oeyen S., Mayrhofer M., Whitington T., van Dam P.J., Van Oyen P., Ghysel C., Ampe J., Ost P., Demey W., et al. Outperforms Other Androgen Receptor Biomarkers to Predict Abiraterone or Enzalutamide Outcome in Metastatic Castration-Resistant Prostate Cancer. Clin. Cancer Res. 2019;25:1766–1773. doi: 10.1158/1078-0432.CCR-18-1943. PubMed DOI PMC

Smith M.R., Thomas S., Gormley M., Chowdhury S., Olmos D., Oudard S., Feng F.Y., Rajpurohit Y., Urtishak K., Ricci D.S., et al. Blood Biomarker Landscape in Patients with High-risk Nonmetastatic Castration-Resistant Prostate Cancer Treated with Apalutamide and Androgen-Deprivation Therapy as They Progress to Metastatic Disease. Clin. Cancer Res. 2021;27:4539–4548. doi: 10.1158/1078-0432.CCR-21-0358. PubMed DOI

Dong B., Fan L., Yang B., Chen W., Li Y., Wu K., Zhang F., Dong H., Cheng H., Pan J., et al. Use of Circulating Tumor DNA for the Clinical Management of Metastatic Castration-Resistant Prostate Cancer: A Multicenter, Real-World Study. J. Natl. Compr. Canc Netw. 2021;19:905–914. doi: 10.6004/jnccn.2020.7663. PubMed DOI

Liu A.J., Kosiorek H.E., Ueberroth B.E., Jaeger E., Ledet E., Kendi A.T., Tzou K., Quevedo F., Choo R., Moore C.N., et al. The impact of genetic aberrations on response to radium-223 treatment for castration-resistant prostate cancer with bone metastases. Prostate. 2022;82:1202–1209. doi: 10.1002/pros.24375. PubMed DOI

Watson A.P., Shabaneh A., Wang J., Dehm S.M., Rao A., Ryan C.J. Triple Aberrant Prostate Cancer (TAPC)—Aggregate role of aberrations in. Am. J. Clin. Exp. Urol. 2020;8:106–115. PubMed PMC

Alshalalfa M., Goglia A.G., Swami N., Nguyen B., Hougen H.Y., Khan A., Kishan A.U., Punnen S., Nguyen P.L., Mahal B.A., et al. Determinants of widespread metastases and of metastatic tropism in patients with prostate cancer: A genomic analysis of primary and metastatic tumors. Urol. Oncol. 2023;41:253.e221–253.e226. doi: 10.1016/j.urolonc.2023.02.006. PubMed DOI PMC

Nizialek E., Lim S.J., Wang H., Isaacsson Velho P., Yegnasubramanian S., Antonarakis E.S. Genomic profiles and clinical outcomes in primary versus secondary metastatic hormone-sensitive prostate cancer. Prostate. 2021;81:572–579. doi: 10.1002/pros.24135. PubMed DOI

Jiménez N., Garcia de Herreros M., Reig Ò., Marín-Aguilera M., Aversa C., Ferrer-Mileo L., García-Esteve S., Rodríguez-Carunchio L., Trias I., Font A., et al. Development and Independent Validation of a Prognostic Gene Expression Signature Based on RB1, PTEN, and TP53 in Metastatic Hormone-sensitive Prostate Cancer Patients. Eur. Urol. Oncol. 2024;7:954–964. doi: 10.1016/j.euo.2023.12.012. PubMed DOI

Jiménez N., Reig Ò., Marín-Aguilera M., Aversa C., Ferrer-Mileo L., Font A., Rodriguez-Vida A., Climent M., Cros S., Chirivella I., et al. Transcriptional Profile Associated with Clinical Outcomes in Metastatic Hormone-Sensitive Prostate Cancer Treated with Androgen Deprivation and Docetaxel. Cancers. 2022;14:4757. doi: 10.3390/cancers14194757. PubMed DOI PMC

Deek M.P., Van der Eecken K., Phillips R., Parikh N.R., Isaacsson Velho P., Lotan T.L., Kishan A.U., Maurer T., Boutros P.C., Hovens C., et al. The Mutational Landscape of Metastatic Castration-sensitive Prostate Cancer: The Spectrum Theory Revisited. Eur. Urol. 2021;80:632–640. doi: 10.1016/j.eururo.2020.12.040. PubMed DOI PMC

Sutera P., Song Y., Shetty A.C., English K., Van der Eecken K., Guler O.C., Wang J., Cao Y., Bazyar S., Verbeke S., et al. Genomic Determinants Associated with Modes of Progression and Patterns of Failure in Metachronous Oligometastatic Castration-sensitive Prostate Cancer. Eur. Urol. Oncol. 2024 doi: 10.1016/j.euo.2024.05.011. in press . PubMed DOI

Quigley D.A., Dang H.X., Zhao S.G., Lloyd P., Aggarwal R., Alumkal J.J., Foye A., Kothari V., Perry M.D., Bailey A.M., et al. Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer. Cell. 2018;175:889. doi: 10.1016/j.cell.2018.10.019. PubMed DOI

Wang R., Xu Q., Guo H., Yang G., Zhang J., Wang H., Xu T., Guo C., Yuan J., He Y., et al. Concordance and Clinical Significance of Genomic Alterations in Progressive Tumor Tissue and Matched Circulating Tumor DNA in Aggressive-variant Prostate Cancer. Cancer Res. Commun. 2023;3:2221–2232. doi: 10.1158/2767-9764.CRC-23-0175. PubMed DOI PMC

Tewari A.K., Cheung A.T.M., Crowdis J., Conway J.R., Camp S.Y., Wankowicz S.A., Livitz D.G., Park J., Lis R.T., Bosma-Moody A., et al. Molecular features of exceptional response to neoadjuvant anti-androgen therapy in high-risk localized prostate cancer. Cell Rep. 2021;36:109665. doi: 10.1016/j.celrep.2021.109665. PubMed DOI

Deek M.P., Van der Eecken K., Sutera P., Deek R.A., Fonteyne V., Mendes A.A., Decaestecker K., Kiess A.P., Lumen N., Phillips R., et al. Long-Term Outcomes and Genetic Predictors of Response to Metastasis-Directed Therapy Versus Observation in Oligometastatic Prostate Cancer: Analysis of STOMP and ORIOLE Trials. J. Clin. Oncol. 2022;40:3377–3382. doi: 10.1200/JCO.22.00644. PubMed DOI PMC

Annala M., Taavitsainen S., Khalaf D.J., Vandekerkhove G., Beja K., Sipola J., Warner E.W., Herberts C., Wong A., Fu S., et al. Evolution of Castration-Resistant Prostate Cancer in ctDNA during Sequential Androgen Receptor Pathway Inhibition. Clin. Cancer Res. 2021;27:4610–4623. doi: 10.1158/1078-0432.CCR-21-1625. PubMed DOI

Gupta S., Halabi S., Kemeny G., Anand M., Giannakakou P., Nanus D.M., George D.J., Gregory S.G., Armstrong A.J. Circulating Tumor Cell Genomic Evolution and Hormone Therapy Outcomes in Men with Metastatic Castration-Resistant Prostate Cancer. Mol. Cancer Res. 2021;19:1040–1050. doi: 10.1158/1541-7786.MCR-20-0975. PubMed DOI PMC

Jayaram A., Wingate A., Wetterskog D., Wheeler G., Sternberg C.N., Jones R., Berruti A., Lefresne F., Lahaye M., Thomas S., et al. Plasma tumor gene conversions after one cycle abiraterone acetate for metastatic castration-resistant prostate cancer: A biomarker analysis of a multicenter international trial. Ann. Oncol. 2021;32:726–735. doi: 10.1016/j.annonc.2021.03.196. PubMed DOI

Alumkal J.J., Sun D., Lu E., Beer T.M., Thomas G.V., Latour E., Aggarwal R., Cetnar J., Ryan C.J., Tabatabaei S., et al. Transcriptional profiling identifies an androgen receptor activity-low, stemness program associated with enzalutamide resistance. Proc. Natl. Acad. Sci. USA. 2020;117:12315–12323. doi: 10.1073/pnas.1922207117. PubMed DOI PMC

Tan W., Zheng T., Wang A., Roacho J., Thao S., Du P., Jia S., Yu J., King B.L., Kohli M. Dynamic changes in gene alterations during chemotherapy in metastatic castrate resistant prostate cancer. Sci. Rep. 2022;12:4672. doi: 10.1038/s41598-022-08520-6. PubMed DOI PMC

Satapathy S., Das C.K., Aggarwal P., Sood A., Parihar A.S., Singh S.K., Mittal B.R. Genomic characterization of metastatic castration-resistant prostate cancer patients undergoing PSMA radioligand therapy: A single-center experience. Prostate. 2023;83:169–178. doi: 10.1002/pros.24450. PubMed DOI

Vanwelkenhuyzen J., Van Bos E., Van Bruwaene S., Lesage K., Maes A., Üstmert S., Lavent F., Beels L., Grönberg H., Ost P., et al. AR and PI3K Genomic Profiling of Cell-free DNA Can Identify Poor Responders to Lutetium-177-PSMA Among Patients with Metastatic Castration-resistant Prostate Cancer. Eur. Urol. Open Sci. 2023;53:63–66. doi: 10.1016/j.euros.2023.05.008. PubMed DOI PMC

Raychaudhuri R., Mo G., Tuchayi A.M., Graham L., Gulati R., Pritchard C.C., Haffner M.C., Yezefski T., Hawley J.E., Cheng H.H., et al. Genomic Correlates of Prostate-Specific Membrane Antigen Expression and Response to. JCO Precis. Oncol. 2024;8:e2300634. doi: 10.1200/PO.23.00634. PubMed DOI PMC

Crumbaker M., Goldstein L.D., Murray D.H., Tao J., Pathmanandavel S., Boulter N., Ratnayake L., Joshua A.M., Kummerfeld S., Emmett L. Circulating Tumour DNA Biomarkers Associated with Outcomes in Metastatic Prostate Cancer Treated with Lutetium-177-PSMA-617. Eur. Urol. Open Sci. 2023;57:30–36. doi: 10.1016/j.euros.2023.08.007. PubMed DOI PMC

Klimovich B., Meyer L., Merle N., Neumann M., König A.M., Ananikidis N., Keber C.U., Elmshäuser S., Timofeev O., Stiewe T. Partial p53 reactivation is sufficient to induce cancer regression. J. Exp. Clin. Cancer Res. 2022;41:80. doi: 10.1186/s13046-022-02269-6. PubMed DOI PMC

Lehmann S., Bykov V.J., Ali D., Andrén O., Cherif H., Tidefelt U., Uggla B., Yachnin J., Juliusson G., Moshfegh A., et al. Targeting p53 in vivo: A first-in-human study with p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer. J. Clin. Oncol. 2012;30:3633–3639. doi: 10.1200/JCO.2011.40.7783. PubMed DOI

Park H., Shapiro G.I., Gao X., Mahipal A., Starr J., Furqan M., Singh P., Ahrorov A., Gandhi L., Ghosh A., et al. Phase Ib study of eprenetapopt (APR-246) in combination with pembrolizumab in patients with advanced or metastatic solid tumors. ESMO Open. 2022;7:100573. doi: 10.1016/j.esmoop.2022.100573. PubMed DOI PMC

Tovar C., Graves B., Packman K., Filipovic Z., Higgins B., Xia M., Tardell C., Garrido R., Lee E., Kolinsky K., et al. MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models. Cancer Res. 2013;73:2587–2597. doi: 10.1158/0008-5472.CAN-12-2807. PubMed DOI

Andreeff M., Kelly K.R., Yee K., Assouline S., Strair R., Popplewell L., Bowen D., Martinelli G., Drummond M.W., Vyas P., et al. Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia. Clin. Cancer Res. 2016;22:868–876. doi: 10.1158/1078-0432.CCR-15-0481. PubMed DOI PMC

Tovar C., Higgins B., Kolinsky K., Xia M., Packman K., Heimbrook D.C., Vassilev L.T. MDM2 antagonists boost antitumor effect of androgen withdrawal: Implications for therapy of prostate cancer. Mol. Cancer. 2011;10:49. doi: 10.1186/1476-4598-10-49. PubMed DOI PMC

Supiot S., Hill R.P., Bristow R.G. Nutlin-3 radiosensitizes hypoxic prostate cancer cells independent of p53. Mol. Cancer Ther. 2008;7:993–999. doi: 10.1158/1535-7163.MCT-07-0442. PubMed DOI

Zhang Y., Xu L., Chang Y., Li Y., Butler W., Jin E., Wang A., Tao Y., Chen X., Liang C., et al. Therapeutic potential of ReACp53 targeting mutant p53 protein in CRPC. Prostate Cancer Prostatic Dis. 2020;23:160–171. doi: 10.1038/s41391-019-0172-z. PubMed DOI PMC