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p53 in the Clinics pp 257–273Cite as

Targeting Mutant p53 for Improved Cancer Therapy

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Abstract

Pharmacological restoration of wild-type activity to mutant p53 has emerged as a promising strategy for improved cancer therapy. This should restore p53-dependent apoptosis in response to oncogenic stress and thus eliminate the tumor. Mutant p53 reactivation may also lead to inhibition of mutant p53 gain-of-function activities that promote tumor growth, and act synergistically with conventional chemotherapeutic agents and radiotherapy. Several small molecules that target mutant p53 and restore wild-type conformation, and/or preferentially target mutant p53-expressing tumor cells, have been identified. Strategies for identification of such compounds include both rational design, based on detailed structural studies of mutant p53, and random screening of chemical libraries using protein or cellular assays. The mutant p53-reactivating compounds PRIMA-1 and APR-246 (PRIMA-1MET) modify cysteines in the p53 core domain by Michael addition. Mutant versions of p53 family members p63 and p73 can be targeted as well. The safety of APR-246 has been tested in a phase I clinical trial. Further studies should address the molecular mechanism of mutant p53 reactivation in more detail and assess clinical antitumor efficacy.

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References

  • Bao W, Chen M, Zhao X, Kumar R, Spinnler C, Thullberg M, Issaeva N, Selivanova G, Stromblad S (2011) PRIMA-1Met/APR-246 induces wild-type p53-dependent suppression of malignant melanoma tumor growth in 3D culture and in vivo. Cell Cycle 10:301–307

    Article  PubMed  CAS  Google Scholar 

  • Boeckler FM, Joerger AC, Jaggi G, Rutherford TJ, Veprintsev DB, Fersht AR (2008) Targeted rescue of a destabilized mutant of p53 by an in silico screened drug. Proc Natl Acad Sci USA 105:10360–10365

    Article  PubMed  CAS  Google Scholar 

  • Bourdon JC (2007) p53 Family isoforms. Curr Pharm Biotechnol 8:332–336

    Article  PubMed  CAS  Google Scholar 

  • Brosh R, Rotter V (2009) When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer 9:701–713

    PubMed  CAS  Google Scholar 

  • Bykov VJ, Issaeva N, Shilov A, Hultcrantz M, Pugacheva E, Chumakov P, Bergman J, Wiman KG, Selivanova G (2002) Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med 8:282–288

    Article  PubMed  CAS  Google Scholar 

  • Bykov VJ, Zache N, Stridh H, Westman J, Bergman J, Selivanova G, Wiman KG (2005a) PRIMA-1(MET) synergizes with cisplatin to induce tumor cell apoptosis. Oncogene 24:3484–3491

    Article  PubMed  CAS  Google Scholar 

  • Bykov VJ, Issaeva N, Zache N, Shilov A, Hultcrantz M, Bergman J, Selivanova G, Wiman KG (2005b) Reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs. J Biol Chem 280:30384–30391

    Article  PubMed  CAS  Google Scholar 

  • Cabello CM, Bair WB III, Lamore SD, Ley S, Bause AS, Azimian S, Wondrak GT (2009) The cinnamon-derived Michael acceptor cinnamic aldehyde impairs melanoma cell proliferation, invasiveness, and tumor growth. Free Radic Biol Med 46:220–231

    Article  PubMed  CAS  Google Scholar 

  • Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M et al (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507–2516

    Article  PubMed  CAS  Google Scholar 

  • Chew EH, Nagle AA, Zhang Y, Scarmagnani S, Palaniappan P, Bradshaw TD, Holmgren A, Westwell AD (2010) Cinnamaldehydes inhibit thioredoxin reductase and induce Nrf2: potential candidates for cancer therapy and chemoprevention. Free Radic Biol Med 48:98–111

    Article  PubMed  CAS  Google Scholar 

  • Chipuk JE, Maurer U, Green DR, Schuler M (2003) Pharmacologic activation of p53 elicits Bax-dependent apoptosis in the absence of transcription. Cancer Cell 4:371–381

    Article  PubMed  CAS  Google Scholar 

  • Chipuk JE, Kuwana T, Bouchier-Hayes L, Droin NM, Newmeyer DD, Schuler M, Green DR (2004) Direct activation of Bax by p53 mediates mitochondrial membrane permeabilization and apoptosis. Science 303:1010–1014

    Article  PubMed  CAS  Google Scholar 

  • Comperat E, Camparo P, Haus R, Chartier-Kastler E, Bart S, Delcourt A, Houlgatte A, Francois R, Capron F, Vieillefond A (2006) Immunohistochemical expression of p63, p53 and MIB-1 in urinary bladder carcinoma. A tissue microarray study of 158 cases. Virchows Arch 448:319–324

    Article  PubMed  CAS  Google Scholar 

  • Corn PG, Kuerbitz SJ, van Noesel MM, Esteller M, Compitello N, Baylin SB, Herman JG (1999) Transcriptional silencing of the p73 gene in acute lymphoblastic leukemia and Burkitt’s lymphoma is associated with 5’ CpG island methylation. Cancer Res 59:3352–3356

    PubMed  CAS  Google Scholar 

  • Demma M, Maxwell E, Ramos R, Liang L, Li C, Hesk D, Rossman R, Mallams A, Doll R, Liu M et al (2010) SCH529074, a small molecule activator of mutant p53, which binds p53 DNA binding domain (DBD), restores growth-suppressive function to mutant p53 and interrupts HDM2-mediated ubiquitination of wild type p53. J Biol Chem 285:10198–10212

    Article  PubMed  CAS  Google Scholar 

  • Di Agostino S, Cortese G, Monti O, Dell’Orso S, Sacchi A, Eisenstein M, Citro G, Strano S, Blandino G (2008) The disruption of the protein complex mutantp53/p73 increases selectively the response of tumor cells to anticancer drugs. Cell Cycle 7:3440–3447

    Article  PubMed  Google Scholar 

  • Di Como CJ, Gaiddon C, Prives C (1999) p73 function is inhibited by tumor-derived p53 mutants in mammalian cells. Mol Cell Biol 19:1438–1449

    PubMed  Google Scholar 

  • Dotsch V, Bernassola F, Coutandin D, Candi E, Melino G (2010) p63 and p73, the ancestors of p53. Cold Spring Harb Perspect Biol 2:a004887

    Article  PubMed  CAS  Google Scholar 

  • Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB (1996) Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 2:561–566

    Article  PubMed  CAS  Google Scholar 

  • Duan W, Gao L, Wu X, Wang L, Nana-Sinkam SP, Otterson GA, Villalona-Calero MA (2010) MicroRNA-34a is an important component of PRIMA-1-induced apoptotic network in human lung cancer cells. Int J Cancer 127:313–320

    PubMed  CAS  Google Scholar 

  • Fang J, Lu J, Holmgren A (2005) Thioredoxin reductase is irreversibly modified by curcumin: a novel molecular mechanism for its anticancer activity. J Biol Chem 280:25284–25290

    Article  PubMed  CAS  Google Scholar 

  • Flores ER (2011) p73 is critical for the persistence of memory. Cell Death Differ 18:381–382

    Article  PubMed  CAS  Google Scholar 

  • Flores ER, Sengupta S, Miller JB, Newman JJ, Bronson R, Crowley D, Yang A, McKeon F, Jacks T (2005) Tumor predisposition in mice mutant for p63 and p73: evidence for broader tumor suppressor functions for the p53 family. Cancer Cell 7:363–373

    Article  PubMed  CAS  Google Scholar 

  • Foster BA, Coffey HA, Morin MJ, Rastinejad F (1999) Pharmacological rescue of mutant p53 conformation and function. Science 286:2507–2510

    Article  PubMed  CAS  Google Scholar 

  • Friedler A, Hansson LO, Veprintsev DB, Freund SM, Rippin TM, Nikolova PV, Proctor MR, Rudiger S, Fersht AR (2002) A peptide that binds and stabilizes p53 core domain: chaperone strategy for rescue of oncogenic mutants. Proc Natl Acad Sci USA 99:937–942

    Article  PubMed  CAS  Google Scholar 

  • Fry DW, Bridges AJ, Denny WA, Doherty A, Greis KD, Hicks JL, Hook KE, Keller PR, Leopold WR, Loo JA et al (1998) Specific, irreversible inactivation of the epidermal growth factor receptor and erbB2, by a new class of tyrosine kinase inhibitor. Proc Natl Acad Sci USA 95:12022–12027

    Article  PubMed  CAS  Google Scholar 

  • Fukushima H, Koga F, Kawakami S, Fujii Y, Yoshida S, Ratovitski E, Trink B, Kihara K (2009) Loss of DeltaNp63alpha promotes invasion of urothelial carcinomas via N-cadherin/Src homology and collagen/extracellular signal-regulated kinase pathway. Cancer Res 69:9263–9270

    Article  PubMed  CAS  Google Scholar 

  • Gaiddon C, Lokshin M, Ahn J, Zhang T, Prives C (2001) A subset of tumor-derived mutant forms of p53 down-regulate p63 and p73 through a direct interaction with the p53 core domain. Mol Cell Biol 21:1874–1887

    Article  PubMed  CAS  Google Scholar 

  • Gambacorti-Passerini C (2008) Part I: milestones in personalised medicine – imatinib. Lancet Oncol 9:600

    Article  PubMed  Google Scholar 

  • Hamamoto T, Gunji S, Tsuji H, Beppu T (1983) Leptomycins A and B, new antifungal antibiotics. I. Taxonomy of the producing strain and their fermentation, purification and characterization. J Antibiot (Tokyo) 36:639–645

    Article  CAS  Google Scholar 

  • Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674

    Article  PubMed  CAS  Google Scholar 

  • Holaska JM, Paschal BM (1998) A cytosolic activity distinct from crm1 mediates nuclear export of protein kinase inhibitor in permeabilized cells. Proc Natl Acad Sci USA 95:14739–14744

    Article  PubMed  CAS  Google Scholar 

  • Hong H, Takahashi K, Ichisaka T, Aoi T, Kanagawa O, Nakagawa M, Okita K, Yamanaka S (2009) Suppression of induced pluripotent stem cell generation by the p53–p21 pathway. Nature 460:1132–1135

    Article  PubMed  CAS  Google Scholar 

  • Hupp TR, Sparks A, Lane DP (1995) Small peptides activate the latent sequence-specific DNA binding function of p53. Cell 83:237–245

    Article  PubMed  CAS  Google Scholar 

  • Issaeva N, Friedler A, Bozko P, Wiman KG, Fersht AR, Selivanova G (2003) Rescue of mutants of the tumor suppressor p53 in cancer cells by a designed peptide. Proc Natl Acad Sci USA 100:13303–13307

    Article  PubMed  CAS  Google Scholar 

  • Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, Birnbaum MJ, Thompson CB (2005) AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 18:283–293

    Article  PubMed  CAS  Google Scholar 

  • Kaar JL, Basse N, Joerger AC, Stephens E, Rutherford TJ, Fersht AR (2010) Stabilization of mutant p53 via alkylation of cysteines and effects on DNA binding. Protein Sci 19:2267–2278

    Article  PubMed  CAS  Google Scholar 

  • Kawamura T, Suzuki J, Wang YV, Menendez S, Morera LB, Raya A, Wahl GM, Belmonte JCI (2009) Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature 460:1140–1144

    Article  PubMed  CAS  Google Scholar 

  • Kawano S, Miller CW, Gombart AF, Bartram CR, Matsuo Y, Asou H, Sakashita A, Said J, Tatsumi E, Koeffler HP (1999) Loss of p73 gene expression in leukemias/lymphomas due to hypermethylation. Blood 94:1113–1120

    PubMed  CAS  Google Scholar 

  • Kim DH, Kim EH, Na HK, Sun Y, Surh YJ (2010) 15-Deoxy-Delta(12,14)-prostaglandin J(2) stabilizes, but functionally inactivates p53 by binding to the cysteine 277 residue. Oncogene 29:2560–2576

    Article  PubMed  CAS  Google Scholar 

  • Kravchenko JE, Ilyinskaya GV, Komarov PG, Agapova LS, Kochetkov DV, Strom E, Frolova EI, Kovriga I, Gudkov AV, Feinstein E, Chumakov PM (2008) Small-molecule RETRA suppresses mutant p53-bearing cancer cells through a p73-dependent salvage pathway. Proc Natl Acad Sci USA 105:6302–6307

    Article  PubMed  CAS  Google Scholar 

  • Kudo N, Matsumori N, Taoka H, Fujiwara D, Schreiner EP, Wolff B, Yoshida M, Horinouchi S (1999) Leptomycin B inactivates CRM1/exportin 1 by covalent modification at a cysteine residue in the central conserved region. Proc Natl Acad Sci USA 96:9112–9117

    Article  PubMed  CAS  Google Scholar 

  • Kwak EL, Sordella R, Bell DW, Godin-Heymann N, Okimoto RA, Brannigan BW, Harris PL, Driscoll DR, Fidias P, Lynch TJ et al (2005) Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci USA 102:7665–7670

    Article  PubMed  CAS  Google Scholar 

  • Lambert JM, Gorzov P, Veprintsev DB, Soderqvist M, Segerback D, Bergman J, Fersht AR, Hainaut P, Wiman KG, Bykov VJ (2009) PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell 15:376–388

    Article  PubMed  CAS  Google Scholar 

  • Lambert JM, Moshfegh A, Hainaut P, Wiman KG, Bykov VJ (2010) Mutant p53 reactivation by PRIMA-1(MET) induces multiple signaling pathways converging on apoptosis. Oncogene 29:1329–1338

    Article  PubMed  CAS  Google Scholar 

  • Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR, Padera RF, Shapiro GI, Baum A, Himmelsbach F et al (2008) BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models. Oncogene 27:4702–4711

    Article  PubMed  CAS  Google Scholar 

  • Liang Y, Besch-Williford C, Benakanakere I, Thorpe PE, Hyder SM (2011) Targeting mutant p53 protein and the tumor vasculature: an effective combination therapy for advanced breast tumors. Breast Cancer Res Treat 125:407–420

    Article  PubMed  CAS  Google Scholar 

  • Lopez-Lazaro M (2008) Anticancer and carcinogenic properties of curcumin: considerations for its clinical development as a cancer chemopreventive and chemotherapeutic agent. Mol Nutr Food Res 52(Suppl 1):S103–S127

    PubMed  Google Scholar 

  • Manfredi JJ (2010) The Mdm2-p53 relationship evolves: Mdm2 swings both ways as an oncogene and a tumor suppressor. Genes Dev 24:1580–1589

    Article  PubMed  CAS  Google Scholar 

  • Mann K, Hainaut P (2005) Aminothiol WR1065 induces differential gene expression in the presence of wild-type p53. Oncogene 24:3964–3975

    Article  PubMed  CAS  Google Scholar 

  • Marion RM, Strati K, Li H, Murga M, Blanco R, Ortega S, Fernandez-Capetillo O, Serrano M, Blasco MA (2009) A p53-mediated DNA damage response limits reprogramming to ensure iPS cell genomic integrity. Nature 460:1149–1153

    Article  PubMed  CAS  Google Scholar 

  • Martins CP, Brown-Swigart L, Evan GI (2006) Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 127:1323–1334

    Article  PubMed  CAS  Google Scholar 

  • Matheu A, Maraver A, Klatt P, Flores I, Garcia-Cao I, Borras C, Flores JM, Vina J, Blasco MA, Serrano M (2007) Delayed ageing through damage protection by the Arf/p53 pathway. Nature 448:375–379

    Article  PubMed  CAS  Google Scholar 

  • Maurici D, Monti P, Campomenosi P, North S, Frebourg T, Fronza G, Hainaut P (2001) Amifostine (WR2721) restores transcriptional activity of specific p53 mutant proteins in a yeast functional assay. Oncogene 20:3533–3540

    Article  PubMed  CAS  Google Scholar 

  • Michael A (1887) Ueber die Addition von Natriumacetessig- und natriummalonsäureäthern zu den aethern ungesättigter säuren. J Prakt Chem 35:349–356

    Article  Google Scholar 

  • Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P, Moll UM (2003) p53 has a direct apoptogenic role at the mitochondria. Mol Cell 11:577–590

    Article  PubMed  CAS  Google Scholar 

  • Mills AA, Zheng B, Wang XJ, Vogel H, Roop DR, Bradley A (1999) p63 is a p53 homologue required for limb and epidermal morphogenesis. Nature 398:708–713

    Article  PubMed  CAS  Google Scholar 

  • Moll UM, Slade N (2004) p63 and p73: roles in development and tumor formation. Mol Cancer Res 2:371–386

    PubMed  CAS  Google Scholar 

  • Muller PA, Caswell PT, Doyle B, Iwanicki MP, Tan EH, Karim S, Lukashchuk N, Gillespie DA, Ludwig RL, Gosselin P et al (2009) Mutant p53 drives invasion by promoting integrin recycling. Cell 139:1327–1341

    Article  PubMed  Google Scholar 

  • Nishi K, Yoshida M, Fujiwara D, Nishikawa M, Horinouchi S, Beppu T (1994) Leptomycin B targets a regulatory cascade of crm1, a fission yeast nuclear protein, involved in control of higher order chromosome structure and gene expression. J Biol Chem 269:6320–6324

    PubMed  CAS  Google Scholar 

  • North S, Pluquet O, Maurici D, El-Ghissassi F, Hainaut P (2002) Restoration of wild-type conformation and activity of a temperature-sensitive mutant of p53 (p53(V272M)) by the cytoprotective aminothiol WR1065 in the esophageal cancer cell line TE-1. Mol Carcinog 33:181–188

    Article  PubMed  CAS  Google Scholar 

  • Ratovitski E, Trink B, Sidransky D (2006) p63 and p73: teammates or adversaries? Cancer Cell 9:1–2

    Article  PubMed  CAS  Google Scholar 

  • Rippin TM, Bykov VJ, Freund SM, Selivanova G, Wiman KG, Fersht AR (2002) Characterization of the p53-rescue drug CP-31398 in vitro and in living cells. Oncogene 21:2119–2129

    Article  PubMed  CAS  Google Scholar 

  • Rokaeus N, Klein G, Wiman KG, Szekely L, Mattsson K (2007) PRIMA-1(MET) induces nucleolar accumulation of mutant p53 and PML nuclear body-associated proteins. Oncogene 26:982–992

    Article  PubMed  CAS  Google Scholar 

  • Rokaeus N, Shen J, Eckhardt I, Bykov J, Wiman KG, Wilhelm MT (2010) PRIMA-1MET/APR-246 targets mutant forms of p53 family members p63 and p73. Oncogene 29(49):6442–6451

    Article  PubMed  CAS  Google Scholar 

  • Russo D, Ottaggio L, Penna I, Foggetti G, Fronza G, Inga A, Menichini P (2010) PRIMA-1 cytotoxicity correlates with nucleolar localization and degradation of mutant p53 in breast cancer cells. Biochem Biophys Res Commun 402:345–350

    Article  PubMed  CAS  Google Scholar 

  • Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM (1990) The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63:1129–1136

    Article  PubMed  CAS  Google Scholar 

  • Selivanova G, Iotsova V, Okan I, Fritsche M, Strom M, Groner B, Grafstrom RC, Wiman KG (1997) Restoration of the growth suppression function of mutant p53 by a synthetic peptide derived from the p53 C-terminal domain. Nat Med 3:632–638

    Article  PubMed  CAS  Google Scholar 

  • Sharma SV, Bell DW, Settleman J, Haber DA (2007) Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 7:169–181

    Article  PubMed  CAS  Google Scholar 

  • Shen H, Chen ZJ, Zilfou JT, Hopper E, Murphy M, Tew KD (2001) Binding of the aminothiol WR-1065 to transcription factors influences cellular response to anticancer drugs. J Pharmacol Exp Ther 297:1067–1073

    PubMed  CAS  Google Scholar 

  • Shen J, Vakifahmetoglu H, Stridh H, Zhivotovsky B, Wiman KG (2008) PRIMA-1MET induces mitochondrial apoptosis through activation of caspase-2. Oncogene 27:6571–6580

    Article  PubMed  CAS  Google Scholar 

  • Sordella R, Bell DW, Haber DA, Settleman J (2004) Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science 305:1163–1167

    Article  PubMed  CAS  Google Scholar 

  • Soussi T, Wiman KG (2007) Shaping genetic alterations in human cancer: the p53 mutation paradigm. Cancer cell 12:303–312

    Article  PubMed  CAS  Google Scholar 

  • Su X, Chakravarti D, Cho MS, Liu L, Gi YJ, Lin YL, Leung ML, El-Naggar A, Creighton CJ, Suraokar MB et al (2010) TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature 467:986–990

    Article  PubMed  CAS  Google Scholar 

  • Talalay P, De Long MJ, Prochaska HJ (1988) Identification of a common chemical signal regulating the induction of enzymes that protect against chemical carcinogenesis. Proc Natl Acad Sci USA 85:8261–8265

    Article  PubMed  CAS  Google Scholar 

  • Tang X, Zhu Y, Han L, Kim AL, Kopelovich L, Bickers DR, Athar M (2007) CP-31398 restores mutant p53 tumor suppressor function and inhibits UVB-induced skin carcinogenesis in mice. J Clin Invest 117:3753–3764

    Article  PubMed  CAS  Google Scholar 

  • Tomasini R, Tsuchihara K, Wilhelm M, Fujitani M, Rufini A, Cheung CC, Khan F, Itie-Youten A, Wakeham A, Tsao MS et al (2008) TAp73 knockout shows genomic instability with infertility and tumor suppressor functions. Genes Dev 22:2677–2691

    Article  PubMed  CAS  Google Scholar 

  • Urist MJ, Di Como CJ, Lu ML, Charytonowicz E, Verbel D, Crum CP, Ince TA, McKeon FD, Cordon-Cardo C (2002) Loss of p63 expression is associated with tumor progression in bladder cancer. Am J Pathol 161:1199–1206

    Article  PubMed  CAS  Google Scholar 

  • Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, Kong N, Kammlott U, Lukacs C, Klein C et al (2004) In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303:844–848

    Article  PubMed  CAS  Google Scholar 

  • Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, Newman J, Reczek EE, Weissleder R, Jacks T (2007) Restoration of p53 function leads to tumour regression in vivo. Nature 445:661–665

    Article  PubMed  CAS  Google Scholar 

  • Vousden KH, Prives C (2009) Blinded by the light: the growing complexity of p53. Cell 137:413–431

    Article  PubMed  CAS  Google Scholar 

  • Wang W, Takimoto R, Rastinejad F, El-Deiry WS (2003) Stabilization of p53 by CP-31398 inhibits ubiquitination without altering phosphorylation at serine 15 or 20 or MDM2 binding. Mol Cell Biol 23:2171–2181

    Article  PubMed  CAS  Google Scholar 

  • Weinmann L, Wischhusen J, Demma MJ, Naumann U, Roth P, Dasmahapatra B, Weller M (2008) A novel p53 rescue compound induces p53-dependent growth arrest and sensitises glioma cells to Apo2L/TRAIL-induced apoptosis. Cell Death Differ 15:718–729

    Article  PubMed  CAS  Google Scholar 

  • Wiman KG (2010) Pharmacological reactivation of mutant p53: from protein structure to the cancer patient. Oncogene 29:4245–4252

    Article  PubMed  CAS  Google Scholar 

  • Wischhusen J, Naumann U, Ohgaki H, Rastinejad F, Weller M (2003) CP-31398, a novel p53-stabilizing agent, induces p53-dependent and p53-independent glioma cell death. Oncogene 22:8233–8245

    Article  PubMed  CAS  Google Scholar 

  • Wu CH, Coumar MS, Chu CY, Lin WH, Chen YR, Chen CT, Shiao HY, Rafi S, Wang SY, Hsu H et al (2010) Design and synthesis of tetrahydropyridothieno[2,3-d]pyrimidine scaffold based epidermal growth factor receptor (EGFR) kinase inhibitors: the role of side chain chirality and Michael acceptor group for maximal potency. J Med Chem 53:7316–7326

    Article  PubMed  CAS  Google Scholar 

  • Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW (2007) Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445:656–660

    Article  PubMed  CAS  Google Scholar 

  • Yang A, Schweitzer R, Sun D, Kaghad M, Walker N, Bronson RT, Tabin C, Sharpe A, Caput D, Crum C, McKeon F (1999) p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development. Nature 398:714–718

    Article  PubMed  CAS  Google Scholar 

  • Yang A, Walker N, Bronson R, Kaghad M, Oosterwegel M, Bonnin J, Vagner C, Bonnet H, Dikkes P, Sharpe A et al (2000) p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature 404:99–103

    Article  PubMed  CAS  Google Scholar 

  • Yang A, Kaghad M, Caput D, McKeon F (2002) On the shoulders of giants: p63, p73 and the rise of p53. Trends Genet 18:90–95

    Article  PubMed  Google Scholar 

  • Yoshida M, Nishikawa M, Nishi K, Abe K, Horinouchi S, Beppu T (1990) Effects of leptomycin B on the cell cycle of fibroblasts and fission yeast cells. Exp Cell Res 187:150–156

    Article  PubMed  CAS  Google Scholar 

  • Zache N, Lambert JM, Wiman KG, Bykov VJ (2008a) PRIMA-1MET inhibits growth of mouse tumors carrying mutant p53. Cell Oncol 30:411–418

    PubMed  CAS  Google Scholar 

  • Zache N, Lambert JM, Rokaeus N, Shen J, Hainaut P, Bergman J, Wiman KG, Bykov VJ (2008b) Mutant p53 targeting by the low molecular weight compound STIMA-1. Mol Oncol 2:70–80

    Article  PubMed  Google Scholar 

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Acknowledgments

We thank the Swedish Cancer Society (Cancerfonden), the Swedish Medical Research Council (VR), the Cancer Society of Stockholm, the Stockholm County Council (ALF), the EU FP6 framework program, and Karolinska Institutet for generous support. V.J.N.B. and K.G.W. are cofounders and shareholders of the company Aprea AB that develops p53-based cancer therapy including APR-246. K.G.W. is a member of its board.

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Authors and Affiliations

  1. Department of Oncology-Pathology, Cancer Center Karolinska (CCK), Karolinska Institutet, 171 76, Stockholm, Sweden

    Jinfeng Shen, Vladimir J. N. Bykov & Klas G. Wiman

  2. Department of Hematology, Institute of Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA

    Jinfeng Shen

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  1. Jinfeng Shen
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  2. Vladimir J. N. Bykov
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Correspondence to Klas G. Wiman .

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  1. International Prevention Research Instit, 95 cours Lafayette, Lyon, 69006, France

    Pierre Hainaut

  2. International Agency for Cancer Research, 150 Cours Albert-Thomas, Lyon, 69372, France

    Magali Olivier

  3. Cancer Center Karolinska (CCK), Dept. Oncology and Pathology, Karolinska Institute, Karolinska Institutet, Stockholm, 171 76, Sweden

    Klas G. Wiman

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Shen, J., Bykov, V.J.N., Wiman, K.G. (2013). Targeting Mutant p53 for Improved Cancer Therapy. In: Hainaut, P., Olivier, M., Wiman, K. (eds) p53 in the Clinics. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-3676-8_14

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