Restoring guardianship of the genome: Anticancer drug strategies to reverse oncogenic mutant p53 misfolding

  • Husam A. Babikir
    Affiliations
    Laboratory of Experimental and Molecular Neuroimaging (LEMNI), Molecular Imaging Program at Stanford, Stanford University School of Medicine, 300 Pasteur Drive, Grant S-047, Stanford, CA 94305, USA
    Search for articles by this author
  • Rayhaneh Afjei
    Affiliations
    Laboratory of Experimental and Molecular Neuroimaging (LEMNI), Molecular Imaging Program at Stanford, Stanford University School of Medicine, 300 Pasteur Drive, Grant S-047, Stanford, CA 94305, USA
    Search for articles by this author
  • Ramasamy Paulmurugan
    Correspondence
    Corresponding authors.
    Affiliations
    Cellular Pathway Imaging Laboratory (CPIL), Molecular Imaging Program at Stanford, Stanford University School of Medicine, 3155 Porter Drive, Palo Alto, CA 94305, USA
    Search for articles by this author
  • Author Footnotes
    1 Lead contact.
    Tarik F. Massoud
    Correspondence
    Corresponding authors.
    Footnotes
    1 Lead contact.
    Affiliations
    Laboratory of Experimental and Molecular Neuroimaging (LEMNI), Molecular Imaging Program at Stanford, Stanford University School of Medicine, 300 Pasteur Drive, Grant S-047, Stanford, CA 94305, USA
    Search for articles by this author
  • Author Footnotes
    1 Lead contact.
Published:September 19, 2018DOI:https://doi.org/10.1016/j.ctrv.2018.09.004

      Highlights

      • p53 (the guardian of the genome) is essential for maintenance of genetic stability.
      • P53 has been recognized as the most frequently mutated gene in human cancer.
      • A significant number of p53 mutations are structural and cause protein misfolding.
      • Therapeutic options to reactivate wild-type mutant misfolded p53 are underexplored.
      • We discuss lead drug compounds that can restore protein folding and function to p53.

      Abstract

      p53 is a transcription factor that activates numerous genes involved in essential maintenance of genetic stability. P53 is the most frequently mutated gene in human cancer. One third of these mutations are structural, resulting in mutant p53 with a disrupted protein conformation. Here we review current progress in a relatively underexplored aspect of p53-targeted drug development, that is, strategies to reactivate wild-type function of misfolded mutant p53. Unfortunately, most p53-targeted drugs are still at early stages of development and many of them are progressing slowly toward clinical implementation. Significant challenges need to be addressed before clinical translation of new anti-misfolding p53-targeted drugs.

      Keywords

      To read this article in full you will need to make a payment

      Subscribe:

      Subscribe to Cancer Treatment Reviews
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Atz J.
        • Wagner P.
        • Roemer K.
        Function, oligomerization, and conformation of tumor-associated p53 proteins with mutated C-terminus.
        J Cell Biochem. 2000; 76: 572-584
        • Bauer M.R.
        • Joerger A.C.
        • Fersht A.R.
        2-Sulfonylpyrimidines: mild alkylating agents with anticancer activity toward p53-compromised cells.
        Proc Natl Acad Sci USA. 2016; 113: E5271-5280
        • Bauer M.R.
        • Jones R.N.
        • Baud M.G.
        • Wilcken R.
        • Boeckler F.M.
        • Fersht A.R.
        • et al.
        Harnessing fluorine-sulfur contacts and multipolar interactions for the design of p53 mutant Y220C rescue drugs.
        ACS Chem Biol. 2016; 11: 2265-2274
        • Boeckler F.M.
        • Joerger A.C.
        • Jaggi G.
        • Rutherford T.J.
        • Veprintsev D.B.
        • Fersht A.R.
        Targeted rescue of a destabilized mutant of p53 by an in silico screened drug.
        Proc Natl Acad Sci USA. 2008; 105: 10360-10365
        • Bossi G.
        • Lapi E.
        • Strano S.
        • Rinaldo C.
        • Blandino G.
        • Sacchi A.
        Mutant p53 gain of function: reduction of tumor malignancy of human cancer cell lines through abrogation of mutant p53 expression.
        Oncogene. 2006; 25: 304-309
        • Bou-Hanna C.
        • Jarry A.
        • Lode L.
        • Schmitz I.
        • Schulze-Osthoff K.
        • Kury S.
        • et al.
        Acute cytotoxicity of MIRA-1/NSC19630, a mutant p53-reactivating small molecule, against human normal and cancer cells via a caspase-9-dependent apoptosis.
        Cancer Lett. 2015; 359: 211-217
        • Bressac B.
        • Kew M.
        • Wands J.
        • Ozturk M.
        Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa.
        Nature. 1991; 350: 429-431
        • Bullock A.N.
        • Henckel J.
        • Fersht A.R.
        Quantitative analysis of residual folding and DNA binding in mutant p53 core domain: definition of mutant states for rescue in cancer therapy.
        Oncogene. 2000; 19: 1245-1256
        • Bunz F.
        • Dutriaux A.
        • Lengauer C.
        • Waldman T.
        • Zhou S.
        • Brown J.P.
        • Sedivy J.M.
        • Kinzler K.W.
        • Vogelstein B.
        Requirement for p53 and p21 to sustain G2 arrest after DNA damage.
        Science. 1998; 282: 1497-1501
        • Bykov V.J.
        • Issaeva N.
        • Selivanova G.
        • Wiman K.G.
        Mutant p53-dependent growth suppression distinguishes PRIMA-1 from known anticancer drugs: a statistical analysis of information in the National Cancer Institute database.
        Carcinogenesis. 2002; 23: 2011-2018
        • Bykov V.J.
        • Issaeva N.
        • Shilov A.
        • Hultcrantz M.
        • Pugacheva E.
        • Chumakov P.
        • et al.
        Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound.
        Nat Med. 2002; 8: 282-288
        • Bykov V.J.
        • Issaeva N.
        • Zache N.
        • Shilov A.
        • Hultcrantz M.
        • Bergman J.
        • et al.
        Reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs.
        J Biol Chem. 2005; 280: 30384-30391
        • Bykov V.J.
        • Zache N.
        • Stridh H.
        • Westman J.
        • Bergman J.
        • Selivanova G.
        • et al.
        PRIMA-1(MET) synergizes with cisplatin to induce tumor cell apoptosis.
        Oncogene. 2005; 24: 3484-3491
        • Cadwell C.
        • Zambetti G.P.
        The effects of wild-type p53 tumor suppressor activity and mutant p53 gain-of-function on cell growth.
        Gene. 2001; 277: 15-30
        • Camacho C.J.
        • Thirumalai D.
        Modeling the role of disulfide bonds in protein folding: entropic barriers and pathways.
        Proteins. 1995; 22: 27-40
        • Chen J.
        • Marechal V.
        • Levine A.J.
        Mapping of the p53 and mdm-2 interaction domains.
        Mol Cell Biol. 1993; 13: 4107-4114
        • Chen L.
        • Willis S.N.
        • Wei A.
        • Smith B.J.
        • Fletcher J.I.
        • Hinds M.G.
        • et al.
        Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function.
        Mol Cell. 2005; 17: 393-403
        • Cho Y.
        • Gorina S.
        • Jeffrey P.D.
        • Pavletich N.P.
        Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations.
        Science. 1994; 265: 346-355
        • Dearth L.R.
        • Qian H.
        • Wang T.
        • Baroni T.E.
        • Zeng J.
        • Chen S.W.
        • et al.
        Inactive full-length p53 mutants lacking dominant wild-type p53 inhibition highlight loss of heterozygosity as an important aspect of p53 status in human cancers.
        Carcinogenesis. 2007; 28: 289-298
        • Demma M.
        • Maxwell E.
        • Ramos R.
        • Liang L.
        • Li C.
        • Hesk D.
        • et al.
        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. 2010; 285: 10198-10212
        • Demma M.J.
        • Wong S.
        • Maxwell E.
        • Dasmahapatra B.
        CP-31398 restores DNA-binding activity to mutant p53 in vitro but does not affect p53 homologs p63 and p73.
        J Biol Chem. 2004; 279: 45887-45896
        • el-Deiry W.S.
        • Kern S.E.
        • Pietenpol J.A.
        • Kinzler K.W.
        • Vogelstein B.
        Definition of a consensus binding site for p53.
        Nat Genet. 1992; 1: 45-49
        • Eliyahu D.
        • Raz A.
        • Gruss P.
        • Givol D.
        • Oren M.
        Participation of p53 cellular tumour antigen in transformation of normal embryonic cells.
        Nature. 1984; 312: 646-649
        • Emerling B.M.
        • Hurov J.B.
        • Poulogiannis G.
        • Tsukazawa K.S.
        • Choo-Wing R.
        • Wulf G.M.
        • et al.
        Depletion of a putatively druggable class of phosphatidylinositol kinases inhibits growth of p53-null tumors.
        Cell. 2013; 155: 844-857
        • Finlay C.A.
        • Hinds P.W.
        • Tan T.H.
        • Eliyahu D.
        • Oren M.
        • Levine A.J.
        Activating mutations for transformation by p53 produce a gene product that forms an hsc70-p53 complex with an altered half-life.
        Mol Cell Biol. 1988; 8: 531-539
        • FitzGerald K.
        In vitro display technologies - new tools for drug discovery.
        Drug Discov Today. 2000; 5: 253-258
        • Flores E.R.
        • Tsai K.Y.
        • Crowley D.
        • Sengupta S.
        • Yang A.
        • McKeon F.
        • et al.
        p63 and p73 are required for p53-dependent apoptosis in response to DNA damage.
        Nature. 2002; 416: 560-564
        • Foster B.A.
        • Coffey H.A.
        • Morin M.J.
        • Rastinejad F.
        Pharmacological rescue of mutant p53 conformation and function.
        Science. 1999; 286: 2507-2510
        • Frazier M.W.
        • He X.
        • Wang J.
        • Gu Z.
        • Cleveland J.L.
        • Zambetti G.P.
        Activation of c-myc gene expression by tumor-derived p53 mutants requires a discrete C-terminal domain.
        Mol Cell Biol. 1998; 18: 3735-3743
        • Friedler A.
        • Hansson L.O.
        • Veprintsev D.B.
        • Freund S.M.
        • Rippin T.M.
        • Nikolova P.V.
        • et al.
        A peptide that binds and stabilizes p53 core domain: chaperone strategy for rescue of oncogenic mutants.
        Proc Natl Acad Sci USA. 2002; 99: 937-942
        • Garziera M.
        • Cecchin E.
        • Canzonieri V.
        • Sorio R.
        • Giorda G.
        • Scalone S.
        • et al.
        Identification of Novel somatic.
        Int J Mol Sci. 2018; 19
        • Gordo S.
        • Martos V.
        • Santos E.
        • Menéndez M.
        • Bo C.
        • Giralt E.
        • et al.
        Stability and structural recovery of the tetramerization domain of p53–R337H mutant induced by a designed templating ligand.
        Proc Natl Acad Sci USA. 2008; 105: 16426-16431
        • Gouas D.
        • Shi H.
        • Hainaut P.
        The aflatoxin-induced TP53 mutation at codon 249 (R249S): biomarker of exposure, early detection and target for therapy.
        Cancer Lett. 2009; 286: 29-37
        • Hainaut P.
        • Mann K.
        Zinc binding and redox control of p53 structure and function.
        Antioxid Redox Signal. 2001; 3: 611-623
        • Harper J.W.
        • Adami G.R.
        • Wei N.
        • Keyomarsi K.
        • Elledge S.J.
        The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.
        Cell. 1993; 75: 805-816
        • Higashimoto Y.
        • Asanomi Y.
        • Takakusagi S.
        • Lewis M.S.
        • Uosaki K.
        • Durell S.R.
        • et al.
        Unfolding, aggregation, and amyloid formation by the tetramerization domain from mutant p53 associated with lung cancer.
        Biochemistry. 2006; 45: 1608-1619
        • Honda R.
        • Tanaka H.
        • Yasuda H.
        Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53.
        FEBS Lett. 1997; 420: 25-27
        • Issaeva N.
        • Bozko P.
        • Enge M.
        • Protopopova M.
        • Verhoef L.G.
        • Masucci M.
        • et al.
        Small molecule RITA binds to p53, blocks p53-HDM-2 interaction and activates p53 function in tumors.
        Nat Med. 2004; 10: 1321-1328
        • Issaeva N.
        • Friedler A.
        • Bozko P.
        • Wiman K.G.
        • Fersht A.R.
        • Selivanova G.
        Rescue of mutants of the tumor suppressor p53 in cancer cells by a designed peptide.
        Proc Natl Acad Sci USA. 2003; 100: 13303-13307
        • Izetti P.
        • Hautefeuille A.
        • Abujamra A.L.
        • de Farias C.B.
        • Giacomazzi J.
        • Alemar B.
        • et al.
        PRIMA-1, a mutant p53 reactivator, induces apoptosis and enhances chemotherapeutic cytotoxicity in pancreatic cancer cell lines.
        Invest New Drugs. 2014; 32: 783-794
        • Jafari R.
        • Almqvist H.
        • Axelsson H.
        • Ignatushchenko M.
        • Lundbäck T.
        • Nordlund P.
        • et al.
        The cellular thermal shift assay for evaluating drug target interactions in cells.
        Nat Protoc. 2014; 9: 2100-2122
        • Joerger A.C.
        • Ang H.C.
        • Fersht A.R.
        Structural basis for understanding oncogenic p53 mutations and designing rescue drugs.
        Proc Natl Acad Sci USA. 2006; 103: 15056-15061
        • Joerger A.C.
        • Fersht A.R.
        Structure-function-rescue: the diverse nature of common p53 cancer mutants.
        Oncogene. 2007; 26: 2226-2242
        • Kaar J.L.
        • Basse N.
        • Joerger A.C.
        • Stephens E.
        • Rutherford T.J.
        • Fersht A.R.
        Stabilization of mutant p53 via alkylation of cysteines and effects on DNA binding.
        Protein Sci. 2010; 19: 2267-2278
        • Kandoth C.
        • McLellan M.D.
        • Vandin F.
        • Ye K.
        • Niu B.
        • Lu C.
        • et al.
        Mutational landscape and significance across 12 major cancer types.
        Nature. 2013; 502: 333-339
        • Kastan M.B.
        • Zhan Q.
        • el-Deiry W.S.
        • Carrier F.
        • Jacks T.
        • Walsh W.V.
        • Plunkett B.S.
        • Vogelstein B.
        • Fornace A.J.
        A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia.
        Cell. 1992; 71: 587-597
        • Kracikova M.
        • Akiri G.
        • George A.
        • Sachidanandam R.
        • Aaronson S.A.
        A threshold mechanism mediates p53 cell fate decision between growth arrest and apoptosis.
        Cell Death Differ. 2013; 20: 576-588
        • Kravchenko J.E.
        • Ilyinskaya G.V.
        • Komarov P.G.
        • Agapova L.S.
        • Kochetkov D.V.
        • Strom E.
        • et al.
        Small-molecule RETRA suppresses mutant p53-bearing cancer cells through a p73-dependent salvage pathway.
        Proc Natl Acad Sci USA. 2008; 105: 6302-6307
        • Krayem M.
        • Journe F.
        • Wiedig M.
        • Morandini R.
        • Najem A.
        • Sales F.
        • et al.
        p53 Reactivation by PRIMA-1(Met) (APR-246) sensitises (V600E/K)BRAF melanoma to vemurafenib.
        Eur J Cancer. 2016; 55: 98-110
        • Krayem M.
        • Journe F.
        • Wiedig M.
        • Morandini R.
        • Najem A.
        • Salès F.
        • et al.
        p53 Reactivation by PRIMA-1(Met) (APR-246) sensitises (V600E/K)BRAF melanoma to vemurafenib.
        Eur J Cancer. 2016; 55: 98-110
        • Krug L.M.
        • Kindler H.L.
        • Calvert H.
        • Manegold C.
        • Tsao A.S.
        • Fennell D.
        • et al.
        Vorinostat in patients with advanced malignant pleural mesothelioma who have progressed on previous chemotherapy (VANTAGE-014): a phase 3, double-blind, randomised, placebo-controlled trial.
        Lancet Oncol. 2015; 16: 447-456
        • Lain S.
        • Hollick J.J.
        • Campbell J.
        • Staples O.D.
        • Higgins M.
        • Aoubala M.
        • et al.
        Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator.
        Cancer Cell. 2008; 13: 454-463
        • Lambert J.M.
        • Gorzov P.
        • Veprintsev D.B.
        • Soderqvist M.
        • Segerback D.
        • Bergman J.
        • et al.
        PRIMA-1 reactivates mutant p53 by covalent binding to the core domain.
        Cancer Cell. 2009; 15: 376-388
        • Lambert J.M.
        • Moshfegh A.
        • Hainaut P.
        • Wiman K.G.
        • Bykov V.J.
        Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis.
        Oncogene. 2010; 29: 1329-1338
        • Lane D.P.
        • Brown C.J.
        • Verma C.
        • Cheok C.F.
        New insights into p53 based therapy.
        Discov Med. 2011; 12: 107-117
        • Lang G.A.
        • Iwakuma T.
        • Suh Y.A.
        • Liu G.
        • Rao V.A.
        • Parant J.M.
        • et al.
        Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome.
        Cell. 2004; 119: 861-872
        • Lehmann S.
        • Bykov V.J.
        • Ali D.
        • Andren O.
        • Cherif H.
        • Tidefelt U.
        • 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
        • Li Q.
        • Lozano G.
        Molecular pathways: targeting Mdm2 and Mdm4 in cancer therapy.
        Clin Cancer Res. 2013; 19: 34-41
        • Li X.L.
        • Zhou J.
        • Chan Z.L.
        • Chooi J.Y.
        • Chen Z.R.
        • Chng W.J.
        PRIMA-1met (APR-246) inhibits growth of colorectal cancer cells with different p53 status through distinct mechanisms.
        Oncotarget. 2015; 6: 36689-36699
        • Li Z.
        • Xu X.
        • Li Y.
        • Zou K.
        • Zhang Z.
        • Liao Y.
        • et al.
        Synergistic antitumor effect of BKM120 with Prima-1Met via inhibiting PI3K/AKT/mTOR and CPSF4/hTERT signaling and reactivating mutant P53.
        Cell Physiol Biochem. 2018; 45: 1772-1786
        • Liang Y.
        • Besch-Williford C.
        • Hyder S.M.
        PRIMA-1 inhibits growth of breast cancer cells by re-activating mutant p53 protein.
        Int J Oncol. 2009; 35: 1015-1023
        • Liu X.
        • Wilcken R.
        • Joerger A.C.
        • Chuckowree I.S.
        • Amin J.
        • Spencer J.
        • et al.
        Small molecule induced reactivation of mutant p53 in cancer cells.
        Nucl Acids Res. 2013; 41: 6034-6044
        • Loh S.N.
        The missing zinc: p53 misfolding and cancer.
        Metallomics. 2010; 2: 442-449
        • Lohrum M.A.
        • Ludwig R.L.
        • Kubbutat M.H.
        • Hanlon M.
        • Vousden K.H.
        Regulation of HDM2 activity by the ribosomal protein L11.
        Cancer Cell. 2003; 3: 577-587
        • Lu T.
        • Zou Y.
        • Xu G.
        • Potter J.A.
        • Taylor G.L.
        • Duan Q.
        • et al.
        PRIMA-1Met suppresses colorectal cancer independent of p53 by targeting MEK.
        Oncotarget. 2016; 7: 83017-83030
        • Lujambio A.
        • Akkari L.
        • Simon J.
        • Grace D.
        • Tschaharganeh D.F.
        • Bolden J.E.
        • et al.
        Non-cell-autonomous tumor suppression by p53.
        Cell. 2013; 153: 449-460
        • Ma C.X.
        • Cai S.
        • Li S.
        • Ryan C.E.
        • Guo Z.
        • Schaiff W.T.
        • et al.
        Targeting Chk1 in p53-deficient triple-negative breast cancer is therapeutically beneficial in human-in-mouse tumor models.
        J Clin Invest. 2012; 122: 1541-1552
        • Ma C.X.
        • Ellis M.J.
        • Petroni G.R.
        • Guo Z.
        • Cai S.R.
        • Ryan C.E.
        • et al.
        A phase II study of UCN-01 in combination with irinotecan in patients with metastatic triple negative breast cancer.
        Breast Cancer Res Treat. 2013; 137: 483-492
        • Madan E.
        • Parker T.M.
        • Bauer M.R.
        • Dhiman A.
        • Pelham C.J.
        • Nagane M.
        • et al.
        The curcumin analog HO-3867 selectively kills cancer cells by converting mutant p53 protein to transcriptionally active wildtype p53.
        J Biol Chem. 2018; 293: 4262-4272
        • Mantovani F.
        • Walerych D.
        • Sal G.D.
        Targeting mutant p53 in cancer: a long road to precision therapy.
        FEBS J. 2017; 284: 837-850
        • Maslon M.M.
        • Hupp T.R.
        Drug discovery and mutant p53.
        Trends Cell Biol. 2010; 20: 542-555
        • Mello S.S.
        • Valente L.J.
        • Raj N.
        • Seoane J.A.
        • Flowers B.M.
        • McClendon J.
        • et al.
        A p53 super-tumor suppressor reveals a tumor suppressive p53-Ptpn14-Yap axis in pancreatic cancer.
        Cancer Cell. 2017; 32: 460-473.e466
        • Mohell N.
        • Alfredsson J.
        • Fransson Å.
        • Uustalu M.
        • Byström S.
        • Gullbo J.
        • et al.
        APR-246 overcomes resistance to cisplatin and doxorubicin in ovarian cancer cells.
        Cell Death Dis. 2015; 6: e1794
        • Muller P.A.
        • Vousden K.H.
        Mutant p53 in cancer: new functions and therapeutic opportunities.
        Cancer Cell. 2014; 25: 304-317
        • Nechushtan H.
        • Hamamreh Y.
        • Nidal S.
        • Gotfried M.
        • Baron A.
        • Shalev Y.I.
        • et al.
        A phase IIb trial assessing the addition of disulfiram to chemotherapy for the treatment of metastatic non-small cell lung cancer.
        Oncologist. 2015; 20: 366-367
        • Network C.G.A.
        Comprehensive molecular portraits of human breast tumours.
        Nature. 2012; 490: 61-70
        • Nikolova P.V.
        • Wong K.B.
        • DeDecker B.
        • Henckel J.
        • Fersht A.R.
        Mechanism of rescue of common p53 cancer mutations by second-site suppressor mutations.
        EMBO J. 2000; 19: 370-378
        • Olivier M.
        • Langerød A.
        • Carrieri P.
        • Bergh J.
        • Klaar S.
        • Eyfjord J.
        • et al.
        The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer.
        Clin Cancer Res. 2006; 12: 1157-1167
        • Olivos III, D.J.
        • Mayo L.D.
        Emerging non-canonical functions and regulation by p53: p53 and stemness.
        Int J Mol Sci. 2016; 17: 1982
        • Origanti S.
        • Cai S.R.
        • Munir A.Z.
        • White L.S.
        • Piwnica-Worms H.
        Synthetic lethality of Chk1 inhibition combined with p53 and/or p21 loss during a DNA damage response in normal and tumor cells.
        Oncogene. 2013; 32: 577-588
        • Pant V.
        • Lozano G.
        Limiting the power of p53 through the ubiquitin proteasome pathway.
        Genes Dev. 2014; 28: 1739-1751
        • Parrales A.
        • Iwakuma T.
        Targeting oncogenic mutant p53 for cancer therapy.
        Front Oncol. 2015; 5: 288
        • Paulmurugan R.
        • Afjei R.
        • Sekar T.V.
        • Babikir H.A.
        • Massoud T.F.
        A protein folding molecular imaging biosensor monitors the effects of drugs that restore mutant p53 structure and its downstream function in glioblastoma cells.
        Oncotarget. 2018; 9: 21495-21511
        • Peifer M.
        • Fernandez-Cuesta L.
        • Sos M.L.
        • George J.
        • Seidel D.
        • Kasper L.H.
        • et al.
        Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer.
        Nat Genet. 2012; 44: 1104-1110
        • Peltonen K.
        • Colis L.
        • Liu H.
        • Jaamaa S.
        • Moore H.M.
        • Enback J.
        • et al.
        Identification of novel p53 pathway activating small-molecule compounds reveals unexpected similarities with known therapeutic agents.
        PLoS ONE. 2010; 5: e12996
        • Pfeifer G.P.
        • Denissenko M.F.
        • Olivier M.
        • Tretyakova N.
        • Hecht S.S.
        • Hainaut P.
        Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers.
        Oncogene. 2002; 21: 7435-7451
        • Pintus S.S.
        • Ivanisenko N.V.
        • Demenkov P.S.
        • Ivanisenko T.V.
        • Ramachandran S.
        • Kolchanov N.A.
        • et al.
        The substitutions G245C and G245D in the Zn(2+)-binding pocket of the p53 protein result in differences of conformational flexibility of the DNA-binding domain.
        J Biomol Struct Dyn. 2013; 31: 78-86
        • Ramalingam S.
        • Goss G.
        • Rosell R.
        • Schmid-Bindert G.
        • Zaric B.
        • Andric Z.
        • et al.
        A randomized phase II study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel in second-line therapy of advanced non-small cell lung cancer (GALAXY-1).
        Ann Oncol. 2015; 26: 1741-1748
        • Rao C.V.
        • Patlolla J.M.
        • Qian L.
        • Zhang Y.
        • Brewer M.
        • Mohammed A.
        • et al.
        Chemopreventive effects of the p53-modulating agents CP-31398 and Prima-1 in tobacco carcinogen-induced lung tumorigenesis in A/J mice.
        Neoplasia. 2013; 15: 1018-1027
        • Ray-Coquard I.
        • Blay J.Y.
        • Italiano A.
        • Le Cesne A.
        • Penel N.
        • Zhi J.
        • et al.
        Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study.
        Lancet Oncol. 2012; 13: 1133-1140
        • Rippin T.M.
        • Bykov V.J.
        • Freund S.M.
        • Selivanova G.
        • Wiman K.G.
        • Fersht A.R.
        Characterization of the p53-rescue drug CP-31398 in vitro and in living cells.
        Oncogene. 2002; 21: 2119-2129
        • Rivlin N.
        • Brosh R.
        • Oren M.
        • Rotter V.
        Mutations in the p53 tumor suppressor gene: important milestones at the various steps of tumorigenesis.
        Genes Cancer. 2011; 2: 466-474
        • Rodriguez O.C.
        • Choudhury S.
        • Kolukula V.
        • Vietsch E.E.
        • Catania J.
        • Preet A.
        • et al.
        Dietary downregulation of mutant p53 levels via glucose restriction: mechanisms and implications for tumor therapy.
        Cell Cycle. 2012; 11: 4436-4446
        • Roh J.L.
        • Kang S.K.
        • Minn I.
        • Califano J.A.
        • Sidransky D.
        • Koch W.M.
        p53-Reactivating small molecules induce apoptosis and enhance chemotherapeutic cytotoxicity in head and neck squamous cell carcinoma.
        Oral Oncol. 2011; 47: 8-15
        • Rufini A.
        • Tucci P.
        • Celardo I.
        • Melino G.
        Senescence and aging: the critical roles of p53.
        Oncogene. 2013; 32: 5129-5143
        • Saha M.N.
        • Chen Y.
        • Chen M.H.
        • Chen G.
        • Chang H.
        Small molecule MIRA-1 induces in vitro and in vivo anti-myeloma activity and synergizes with current anti-myeloma agents.
        Br J Cancer. 2014; 110: 2224-2231
        • Saha M.N.
        • Jiang H.
        • Yang Y.
        • Reece D.
        • Chang H.
        PRIMA-1Met/APR-246 displays high antitumor activity in multiple myeloma by induction of p73 and Noxa.
        Mol Cancer Ther. 2013; 12: 2331-2341
        • Saha M.N.
        • Qiu L.
        • Chang H.
        Targeting p53 by small molecules in hematological malignancies.
        J Hematol Oncol. 2013; 6: 23
        • Sakamuro D.
        • Sabbatini P.
        • White E.
        • Prendergast G.C.
        The polyproline region of p53 is required to activate apoptosis but not growth arrest.
        Oncogene. 1997; 15: 887-898
        • Schlereth K.
        • Charles J.P.
        • Bretz A.C.
        • Stiewe T.
        Life or death: p53-induced apoptosis requires DNA binding cooperativity.
        Cell Cycle. 2010; 9: 4068-4076
        • Scian M.J.
        • Stagliano K.E.
        • Ellis M.A.
        • Hassan S.
        • Bowman M.
        • Miles M.F.
        • et al.
        Modulation of gene expression by tumor-derived p53 mutants.
        Cancer Res. 2004; 64: 7447-7454
        • Selivanova G.
        • Iotsova V.
        • Okan I.
        • Fritsche M.
        • Strom M.
        • Groner B.
        • et al.
        Restoration of the growth suppression function of mutant p53 by a synthetic peptide derived from the p53 C-terminal domain.
        Nat Med. 1997; 3: 632-638
        • Shah S.P.
        • Roth A.
        • Goya R.
        • Oloumi A.
        • Ha G.
        • Zhao Y.
        • et al.
        The clonal and mutational evolution spectrum of primary triple-negative breast cancers.
        Nature. 2012; 486: 395-399
        • Simabuco F.M.
        • Morale M.G.
        • Pavan I.C.B.
        • Morelli A.P.
        • Silva F.R.
        • Tamura R.E.
        p53 and metabolism: from mechanism to therapeutics.
        Oncotarget. 2018; 9: 23780-23823
        • Strano S.
        • Dell'Orso S.
        • Mongiovi A.M.
        • Monti O.
        • Lapi E.
        • Di Agostino S.
        • et al.
        Mutant p53 proteins: between loss and gain of function.
        Head Neck. 2007; 29: 488-496
        • Suh Y.A.
        • Post S.M.
        • Elizondo-Fraire A.C.
        • Maccio D.R.
        • Jackson J.G.
        • El-Naggar A.K.
        • et al.
        Multiple stress signals activate mutant p53 in vivo.
        Cancer Res. 2011; 71: 7168-7175
        • Synnott N.C.
        • Bauer M.R.
        • Madden S.
        • Murray A.
        • Klinger R.
        • O'Donovan N.
        • et al.
        Mutant p53 as a therapeutic target for the treatment of triple-negative breast cancer: preclinical investigation with the anti-p53 drug, PK11007.
        Cancer Lett. 2018; 414: 99-106
        • Tal P.
        • Eizenberger S.
        • Cohen E.
        • Goldfinger N.
        • Pietrokovski S.
        • Oren M.
        • et al.
        Cancer therapeutic approach based on conformational stabilization of mutant p53 protein by small peptides.
        Oncotarget. 2016; 7: 11817-11837
        • Tessoulin B.
        • Descamps G.
        • Moreau P.
        • Maiga S.
        • Lode L.
        • Godon C.
        • et al.
        PRIMA-1Met induces myeloma cell death independent of p53 by impairing the GSH/ROS balance.
        Blood. 2014; 124: 1626-1636
        • Vogelstein B.
        • Lane D.
        • Levine A.J.
        Surfing the p53 network.
        Nature. 2000; 408: 307-310
        • Walerych D.
        • Lisek K.
        • Sommaggio R.
        • Piazza S.
        • Ciani Y.
        • Dalla E.
        • et al.
        Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer.
        Nat Cell Biol. 2016; 18: 897-909
        • Wang Z.
        • Sun Y.
        Targeting p53 for novel anticancer therapy.
        Transl Oncol. 2010; 3: 1-12
        • Wassman C.D.
        • Baronio R.
        • Demir Ö.
        • Wallentine B.D.
        • Chen C.K.
        • Hall L.V.
        • et al.
        Computational identification of a transiently open L1/S3 pocket for reactivation of mutant p53.
        Nat Commun. 2013; 4: 1407
      1. WHO's International Agency for Research on Cancer, http://p53.iarc.fr/ [accessed 16 September, 2018].

        • Wiman K.G.
        Strategies for therapeutic targeting of the p53 pathway in cancer.
        Cell Death Differ. 2006; 13: 921-926
        • Wischhusen J.
        • Naumann U.
        • Ohgaki H.
        • Rastinejad F.
        • Weller M.
        CP-31398, a novel p53-stabilizing agent, induces p53-dependent and p53-independent glioma cell death.
        Oncogene. 2003; 22: 8233-8245
        • Xiao G.
        • Chicas A.
        • Olivier M.
        • Taya Y.
        • Tyagi S.
        • Kramer F.R.
        • et al.
        A DNA damage signal is required for p53 to activate gadd45.
        Cancer Res. 2000; 60: 1711-1719
        • Xue W.
        • Zender L.
        • Miething C.
        • Dickins R.A.
        • Hernando E.
        • Krizhanovsky V.
        • et al.
        Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas.
        Nature. 2007; 445: 656-660
        • Yu X.
        • Blanden A.
        • Tsang A.T.
        • Zaman S.
        • Liu Y.
        • Gilleran J.
        • et al.
        Thiosemicarbazones functioning as zinc metallochaperones to reactivate mutant p53.
        Mol Pharmacol. 2017; 91: 567-575
        • Yu X.
        • Blanden A.R.
        • Narayanan S.
        • Jayakumar L.
        • Lubin D.
        • Augeri D.
        • et al.
        Small molecule restoration of wildtype structure and function of mutant p53 using a novel zinc-metallochaperone based mechanism.
        Oncotarget. 2014; 5: 8879-8892
        • Yu X.
        • Vazquez A.
        • Levine A.J.
        • Carpizo D.R.
        Allele-specific p53 mutant reactivation.
        Cancer Cell. 2012; 21: 614-625
        • Yu Y.
        • Kalinowski D.S.
        • Kovacevic Z.
        • Siafakas A.R.
        • Jansson P.J.
        • Stefani C.
        • et al.
        Thiosemicarbazones from the old to new: iron chelators that are more than just ribonucleotide reductase inhibitors.
        J Med Chem. 2009; 52: 5271-5294
        • Zache N.
        • Lambert J.M.
        • Rokaeus N.
        • Shen J.
        • Hainaut P.
        • Bergman J.
        • et al.
        Mutant p53 targeting by the low molecular weight compound STIMA-1.
        Mol Oncol. 2008; 2: 70-80
        • Zache N.
        • Lambert J.M.
        • Rökaeus N.
        • Shen J.
        • Hainaut P.
        • Bergman J.
        • et al.
        Mutant p53 targeting by the low molecular weight compound STIMA-1.
        Mol Oncol. 2008; 2: 70-80
        • Zambetti G.P.
        The p53 mutation “gradient effect” and its clinical implications.
        J Cell Physiol. 2007; 213: 370-373
        • Zandi R.
        • Selivanova G.
        • Christensen C.L.
        • Gerds T.A.
        • Willumsen B.M.
        • Poulsen H.S.
        PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53.
        Clin Cancer Res. 2011; 17: 2830-2841