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  • Review Article
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Targeting mutant p53 for efficient cancer therapy

Nature Reviews Cancer volume 18, pages 89–102 (2018)Cite this article

Subjects

Key Points

  • The TP53 tumour suppressor gene is mutated in close to half of all human tumours

  • Most TP53 mutations are missense mutations leading to single amino acid substitutions in the p53 protein

  • Small molecules that reactivate missense-mutant p53 and induce tumour cell death have been identified by various approaches

  • Two mutant-p53-reactivating compounds are being tested in clinical trials

  • Reactivation of nonsense-mutant TP53 by induction of translational readthrough has been demonstrated with aminoglycoside antibiotics

  • Novel anticancer drugs that reactivate mutant p53 should have wide clinical applicability

Abstract

The tumour suppressor gene TP53 is the most frequently mutated gene in cancer. Wild-type p53 can suppress tumour development by multiple pathways. However, mutation of TP53 and the resultant inactivation of p53 allow evasion of tumour cell death and rapid tumour progression. The high frequency of TP53 mutation in tumours has prompted efforts to restore normal function of mutant p53 and thereby trigger tumour cell death and tumour elimination. Small molecules that can reactivate missense-mutant p53 protein have been identified by different strategies, and two compounds are being tested in clinical trials. Novel approaches for targeting TP53 nonsense mutations are also underway. This Review discusses recent progress in pharmacological reactivation of mutant p53 and highlights problems and promises with these strategies.

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Figure 1: p53 responds to oncogenic stress at early stages of tumour development.
Figure 2: Structure of the p53 core domain bound to DNA.
Figure 3: Refolding and reactivation of missense-mutant p53.
Figure 4: Induction of translational readthrough of nonsense-mutant TP53.

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References

  1. Vousden, K. H. & Prives, C. Blinded by the light: the growing complexity of p53. Cell 137, 413–431 (2009).

    CAS  PubMed  Google Scholar 

  2. Jiang, L. et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature 520, 57–62 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Gao, M., Monian, P., Quadri, N., Ramasamy, R. & Jiang, X. Glutaminolysis and transferrin regulate ferroptosis. Mol. Cell 59, 298–308 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Jennis, M. et al. An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model. Genes Dev. 30, 918–930 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Berkers, C. R., Maddocks, O. D., Cheung, E. C., Mor, I. & Vousden, K. H. Metabolic regulation by p53 family members. Cell Metab. 18, 617–633 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Bartkova, J. et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 434, 864–870 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Gorgoulis, V. G. et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434, 907–913 (2005).

    Article  CAS  PubMed  Google Scholar 

  8. Halazonetis, T. D., Gorgoulis, V. G. & Bartek, J. An oncogene-induced DNA damage model for cancer development. Science 319, 1352–1355 (2008).

    Article  CAS  PubMed  Google Scholar 

  9. Hollstein, M., Sidransky, D., Vogelstein, B. & Harris, C. C. p53 mutations in human cancers. Science 253, 49–53 (1991).

    Article  CAS  PubMed  Google Scholar 

  10. Malkin, D. et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250, 1233–1238 (1990).

    Article  CAS  PubMed  Google Scholar 

  11. Donehower, L. A. et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215–221 (1992).

    CAS  PubMed  Google Scholar 

  12. Brady, C. A. et al. Distinct p53 transcriptional programs dictate acute DNA-damage responses and tumor suppression. Cell 145, 571–583 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Li, T. et al. Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence. Cell 149, 1269–1283 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Valente, L. J. et al. p53 efficiently suppresses tumor development in the complete absence of its cell-cycle inhibitory and proapoptotic effectors p21, Puma, and Noxa. Cell Rep. 3, 1339–1345 (2013).

    Article  CAS  PubMed  Google Scholar 

  15. Bieging, K. T., Mello, S. S. & Attardi, L. D. Unravelling mechanisms of p53-mediated tumour suppression. Nat. Rev. Cancer 14, 359–370 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Andrysik, Z. et al. Identification of a core TP53 transcriptional progrma with highly distrivuted tumor suppressive activity. Genome Res. 27, 1645–1657 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Kandoth, C. et al. Mutational landscape and significance across 12 major cancer types. Nature 502, 333–339 (2013).

    PubMed  PubMed Central  CAS  Google Scholar 

  18. Soussi, T. & Wiman, K. G. TP53: an oncogene in disguise. Cell Death Differ. 22, 1239–1249 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  20. Muller, P. A. & Vousden, K. H. Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell 25, 304–317 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Lang, G. A. et al. Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. Cell 119, 861–872 (2004).

    Article  CAS  PubMed  Google Scholar 

  22. Olive, K. P. et al. Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. Cell 119, 847–860 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Morton, J. P. et al. Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer. Proc. Natl Acad. Sci. USA 107, 246–251 (2010).

    Article  CAS  PubMed  Google Scholar 

  24. Leroy, B., Anderson, M. & Soussi, T. TP53 mutations in human cancer: database reassessment and prospects for the next decade. Hum. Mutat. 35, 672–688 (2014).

    Article  CAS  PubMed  Google Scholar 

  25. Bouaoun, L. et al. TP53 variations in human cancers: new lessons from the IARC TP53 database and genomics data. Hum. Mutat. 37, 865–876 (2016).

    Article  CAS  PubMed  Google Scholar 

  26. Ang, H. C., Joerger, A. C., Mayer, S. & Fersht, A. R. Effects of common cancer mutations on stability and DNA binding of full-length p53 compared with isolated core domains. J. Biol. Chem. 281, 21934–21941 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Cho, Y., Gorina, S., Jeffrey, P. D. & Pavletich, N. P. Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. Science 265, 346–355 (1994).

    Article  CAS  PubMed  Google Scholar 

  28. 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 19, 1245–1256 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Shi, H., Calvez, F. L., Olivier, M. & Hainaut, P. in 25 years of p53 research ( eds Hainaut, P., Wiman, K. G. ) 293–319 (Springer, 2005).

  30. Soussi, T. & Wiman, K. G. Shaping genetic alterations in human cancer: the p53 mutation paradigm. Cancer Cell 12, 303–312 (2007).

    Article  CAS  PubMed  Google Scholar 

  31. Martins, C. P., Brown-Swigart, L. & Evan, G. I. Modeling the therapeutic efficacy of p53 restoration in tumors. Cell 127, 1323–1334 (2006). This is one of three seminal studies showing that reactivation of p53 expression in vivo causes tumour regression. Restoration of p53 expression triggered rapid apoptosis and increased survival in an Eμ- Myc lymphoma model.

    Article  CAS  PubMed  Google Scholar 

  32. Ventura, A. et al. Restoration of p53 function leads to tumour regression in vivo. Nature 445, 661–665 (2007). This is one of three seminal studies showing that reactivation of p53 expression in vivo causes tumour regression. Expression of functional p53 induced apoptosis in lymphomas and cellular senescence in sarcomas.

    Article  CAS  PubMed  Google Scholar 

  33. Xue, W. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007). This is one of three seminal studies showing that reactivation of p53 expression in vivo causes tumour regression. Brief p53 activation triggered cellular senescence and an innate immune response.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Terzian, T. et al. The inherent instability of mutant p53 is alleviated by Mdm2 or p16INK4a loss. Genes Dev. 22, 1337–1344 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Brachmann, R. K., Yu, K., Eby, Y., Pavletich, N. P. & Boeke, J. D. Genetic selection of intragenic suppressor mutations that reverse the effect of common p53 cancer mutations. EMBO J. 17, 1847–1859 (1998).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. 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. 19, 370–378 (2000).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Zhang, W. et al. A temperature-sensitive mutant of human p53. EMBO J. 13, 2535–2544 (1994).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Friedlander, P., Legros, Y., Soussi, T. & Prives, C. Regulation of mutant p53 temperature-sensitive DNA binding. J. Biol. Chem. 271, 25468–25478 (1996).

    Article  CAS  PubMed  Google Scholar 

  39. Michalovitz, D., Halevy, O. & Oren, M. Conditional inhibition of transformation and of cell proliferation by a temperature-sensitive mutant of p53. Cell 62, 671–680 (1990).

    Article  CAS  PubMed  Google Scholar 

  40. Ramqvist, T. et al. Wild-type p53 induces apoptosis in a Burkitt lymphoma (BL) line that carries mutant p53. Oncogene 8, 1495–1500 (1993).

    CAS  PubMed  Google Scholar 

  41. Brown, C. R., Hong-Brown, L. Q. & Welch, W. J. Correcting temperature-sensitive protein folding defects. J. Clin. Invest. 99, 1432–1444 (1997).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Ohnishi, T. et al. Restoration by glycerol of p53-dependent apoptosis in cells bearing the mutant p53 gene. Int. J. Radiat. Biol. 75, 1095–1098 (1999).

    Article  CAS  PubMed  Google Scholar 

  43. Ohnishi, T., Ohnishi, K., Wang, X., Takahashi, A. & Okaichi, K. Restoration of mutant TP53 to normal TP53 function by glycerol as a chemical chaperone. Radiat. Res. 151, 498–500 (1999).

    Article  CAS  PubMed  Google Scholar 

  44. Gekko, K. & Timasheff, S. N. Mechanism of protein stabilization by glycerol: preferential hydration in glycerol-water mixtures. Biochemistry 20, 4667–4676 (1981).

    Article  CAS  PubMed  Google Scholar 

  45. Hupp, T. R., Sparks, A. & Lane, D. P. Small peptides activate the latent sequence-specific DNA binding function of p53. Cell 83, 237–245 (1995).

    Article  CAS  PubMed  Google Scholar 

  46. Selivanova, G. et al. 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 (1997).

    Article  CAS  PubMed  Google Scholar 

  47. Hupp, T. R., Meek, D. W., Midgley, C. A. & Lane, D. P. Regulation of the specific DNA binding function of p53. Cell 71, 875–886 (1992).

    Article  CAS  PubMed  Google Scholar 

  48. Hupp, T. R., Meek, D. W., Midgley, C. A. & Lane, D. P. Activation of the cryptic DNA binding function of mutant forms of p53. Nucleic Acids Res. 21, 3167–3174 (1993).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Anderson, M. E., Woelker, B., Reed, M., Wang, P. & Tegtmeyer, P. Reciprocal interference between the sequence-specific core and nonspecific C-terminal DNA binding domains of p53: implications for regulation. Mol. Cell. Biol. 17, 6255–6264 (1997).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Tyner, S. D. et al. p53 mutant mice that display early ageing-associated phenotypes. Nature 415, 45–53 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Sullivan, A. & Lu, X. ASPP: a new family of oncogenes and tumour suppressor genes. Br. J. Cancer. 96, 196–200 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Friedler, A. et al. A peptide that binds and stabilizes p53 core domain: chaperone strategy for rescue of oncogenic mutants. Proc. Natl Acad. Sci. USA 99, 937–942 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Issaeva, N. et al. Rescue of mutants of the tumor suppressor p53 in cancer cells by a designed peptide. Proc. Natl Acad. Sci. USA 100, 13303–13307 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Friedler, A., Veprintsev, D. B., Hansson, L. O. & Fersht, A. R. Kinetic instability of p53 core domain mutants: implications for rescue by small molecules. J. Biol. Chem. 278, 24108–24112 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Foster, B. A., Coffey, H. A., Morin, M. J. & Rastinejad, F. Pharmacological rescue of mutant p53 conformation and function. Science 286, 2507–2510 (1999).

    Article  CAS  PubMed  Google Scholar 

  56. Rippin, T. M. et al. Characterization of the p53-rescue drug CP-31398 in vitro and in living cells. Oncogene 21, 2119–2129 (2002).

    Article  CAS  PubMed  Google Scholar 

  57. Madka, V. et al. p53-stabilizing agent CP-31398 prevents growth and invasion of urothelial cancer of the bladder in transgenic UPII-SV40T mice. Neoplasia 15, 966–974 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Zache, N. et al. Mutant p53 targeting by the low molecular weight compound STIMA-1. Mol. Oncol. 2, 70–80 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Wang, W., Takimoto, R., Rastinejad, F. & El-Deiry, W. S. 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 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Bykov, V. J. et al. Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat. Med. 8, 282–288 (2002). This study identifies and characterizes the mutant-p53-targeting compound PRIMA-1. The PRIMA-1 analogue APR-246 is being tested in a phase II clinical trial in patients with ovarian cancer.

    Article  CAS  PubMed  Google Scholar 

  61. 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 23, 2011–2018 (2002).

    Article  CAS  PubMed  Google Scholar 

  62. Bykov, V. J. et al. PRIMA-1(MET) synergizes with cisplatin to induce tumor cell apoptosis. Oncogene 24, 3484–3491 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Lambert, J. M. et al. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell 15, 376–388 (2009). This study demonstrates that PRIMA-1 and APR-246 are converted to MQ, a Michael acceptor that binds covalently to cysteine residues in the core domain of p53.

    Article  CAS  PubMed  Google Scholar 

  64. Zache, N., Lambert, J. M., Wiman, K. G. & Bykov, V. J. PRIMA-1MET inhibits growth of mouse tumors carrying mutant p53. Cell. Oncol. 30, 411–418 (2008).

    PubMed  PubMed Central  CAS  Google Scholar 

  65. Zandi, R. et al. PRIMA-1Met/APR-246 induces apoptosis and tumor growth delay in small cell lung cancer expressing mutant p53. Clin. Cancer Res. 17, 2830–2841 (2011).

    Article  CAS  PubMed  Google Scholar 

  66. Liu, D. S. et al. APR-246 potently inhibits tumour growth and overcomes chemoresistance in preclinical models of oesophageal adenocarcinoma. Gut 64, 1506–1516 (2015).

    Article  CAS  PubMed  Google Scholar 

  67. Synnott, N. C. et al. Mutant p53: a novel target for the treatment of patients with triple-negative breast cancer? Int. J. Cancer 140, 234–246 (2017).

    Article  CAS  PubMed  Google Scholar 

  68. Wassman, C. D. et al. Computational identification of a transiently open L1/S3 pocket for reactivation of mutant p53. Nat. Commun. 4, 1407 (2013).

    Article  PubMed  CAS  Google Scholar 

  69. Peng, X. et al. APR-246/PRIMA-1MET inhibits thioredoxin reductase 1 and converts the enzyme to a dedicated NADPH oxidase. Cell Death Dis. 4, e881 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Mohell, N. et al. APR-246 overcomes resistance to cisplatin and doxorubicin in ovarian cancer cells. Cell Death Dis. 6, e1794 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT00900614 (2011).

  72. Lehmann, S. 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. 30, 3633–3639 (2012). This is a presentation of the first clinical study ever with a mutant-p53-reactivating compound. Clinical effects were observed.

    Article  CAS  PubMed  Google Scholar 

  73. Deneberg, S. et al. An open-label phase I dose-finding study of APR-246 in hematological malignancies. Blood Cancer J. 6, e447 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02098343 (2017).

  75. Gourley, C. et al. PISARRO: a EUTROC phase Ib study of APR-246 in combination with carboplatin (C) and pegylated liposomal doxorubicin (PLD) in platinum sensitive relapsed high grade serous ovarian cancer (HGSOC) [abstract]. J. Clin. Oncol. 34 (Suppl. 15), 5571 (2016).

    Article  Google Scholar 

  76. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03072043 (2017).

  77. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02999893 (2017).

  78. Bykov, V. J. et al. Reactivation of mutant p53 and induction of apoptosis in human tumor cells by maleimide analogs. J. Biol. Chem. 280, 30384–30391 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Bykov, V. J. & Wiman, K. G. Mutant p53 reactivation by small molecules makes its way to the clinic. FEBS Lett. 588, 2622–2627 (2014).

    Article  CAS  PubMed  Google Scholar 

  80. 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 110, 2224–2231 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Bou-Hanna, C. 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. 359, 211–217 (2015).

    Article  CAS  PubMed  Google Scholar 

  82. Kaar, J. L. et al. Stabilization of mutant p53 via alkylation of cysteines and effects on DNA binding. Protein Sci. 19, 2267–2278 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. 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 113, E5271–E5280 (2016). This study identifies compounds that bind cysteine-182 and cysteine-277 in p53 through nucleophilic aromatic substitution. The compounds also deplete GSH and induce endoplasmic reticulum stress.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Reddy, N. L., Hill, J., Ye, L., Fernandes, P. B. & Stout, D. M. Identification and structure-activity relationship studies of 3-methylene-2-norbornanone as potent anti-proliferative agents presumably working through p53 mediated apoptosis. Bioorg. Med. Chem. Lett. 14, 5645–5649 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Baronio, R. et al. All-codon scanning identifies p53 cancer rescue mutations. Nucleic Acids Res. 38, 7079–7088 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Yu, X., Vazquez, A., Levine, A. J. & Carpizo, D. R. Allele-specific p53 mutant reactivation. Cancer Cell 21, 614–625 (2012). This paper identifies the thiosemicarbazone NCS319726 (ZMC1) as a reactivator of p53-R175H through a mechanism that involves Zn2+ chelation.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Yu, X. et al. Small molecule restoration of wildtype structure and function of mutant p53 using a novel zinc-metallochaperone based mechanism. Oncotarget 5, 8879–8892 (2014).

    PubMed  PubMed Central  Google Scholar 

  88. Puca, R. et al. Restoring p53 active conformation by zinc increases the response of mutant p53 tumor cells to anticancer drugs. Cell Cycle 10, 1679–1689 (2011).

    Article  CAS  PubMed  Google Scholar 

  89. Blanden, A. R. et al. Synthetic metallochaperone ZMC1 rescues mutant p53 conformation by transporting zinc into cells as an ionophore. Mol. Pharmacol. 87, 825–831 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Salim, K. Y., Vareki, S. M., Danter, W. R. & Koropatnick, J. COTI-2, a new anticancer drug currently under clinical investigation, targets mutant p53 and negatively modulates the PI3K/AKT/mTOR pathway. Eur. J. Cancer 69, S19 (2016).

    Article  Google Scholar 

  91. Salim, K. Y., Vareki, S. M., Danter, W. R. & Koropatnick, J. COTI-2, a novel small molecule that is active against multiple human cancer cell lines in vitro and in vivo. Oncotarget 7, 41363–41379 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  92. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02433626 (2017).

  93. 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 103, 15056–15061 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Boeckler, F. M. et al. Targeted rescue of a destabilized mutant of p53 by an in silico screened drug. Proc. Natl Acad. Sci. USA 105, 10360–10365 (2008). This article describes the design of a compound that binds to a cleft in p53-Y220C and specifically reactivates this mutant.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Liu, X. et al. Small molecule induced reactivation of mutant p53 in cancer cells. Nucleic Acids Res. 41, 6034–6044 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Weinmann, L. et al. 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 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Demma, M. 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. 285, 10198–10212 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Punganuru, S. R. et al. Design and synthesis of a C7-aryl piperlongumine derivative with potent antimicrotubule and mutant p53-reactivating properties. Eur. J. Med. Chem. 107, 233–244 (2016).

    Article  CAS  PubMed  Google Scholar 

  99. Hiraki, M. et al. Small-molecule reactivation of mutant p53 to wild-type-like p53 through the p53-Hsp40 regulatory axis. Chem. Biol. 22, 1206–1216 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Tal, P. et al. Cancer therapeutic approach based on conformational stabilization of mutant p53 protein by small peptides. Oncotarget 7, 11817–11837 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Xu, J. et al. Gain of function of mutant p53 by coaggregation with multiple tumor suppressors. Nat. Chem. Biol. 7, 285–295 (2011).

    Article  CAS  PubMed  Google Scholar 

  102. Levy, C. B. et al. Co-localization of mutant p53 and amyloid-like protein aggregates in breast tumors. Int. J. Biochem. Cell Biol. 43, 60–64 (2011).

    Article  CAS  PubMed  Google Scholar 

  103. Soragni, A. et al. A designed inhibitor of p53 aggregation rescues p53 tumor-suppression in ovarian carcinomas. Cancer Cell 29, 90–103 (2016).

    Article  CAS  PubMed  Google Scholar 

  104. Ferraiuolo, M., Di Agostino, S., Blandino, G. & Strano, S. Oncogenic intra-p53 family member interactions in human cancers. Front. Oncol. 6, 77 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Kravchenko, J. E. et al. Small-molecule RETRA suppresses mutant p53-bearing cancer cells through a p73-dependent salvage pathway. Proc. Natl Acad. Sci. USA 105, 6302–6307 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Alexandrova, E. M. et al. Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment. Nature 523, 352–356 (2015). This article shows that inhibition of mutant p53 expression by inhibiting the chaperone HSP90 can have substantial antitumour effects in mutant Trp53 knock-in mice.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Martinez Molina, D. et al. Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay. Science 341, 84–87 (2013).

    Article  CAS  PubMed  Google Scholar 

  108. Kastenhuber, E. R. & Lowe, S. W. Putting p53 in context. Cell 170, 1062–1078 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Li, X. et al. Emodin enhances cisplatin-induced cytotoxicity in human bladder cancer cells through ROS elevation and MRP1 downregulation. BMC Cancer 16, 578 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Walerych, D. et al. Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer. Nat. Cell Biol. 18, 897–909 (2016).

    Article  CAS  PubMed  Google Scholar 

  111. Fuse, Y. & Kobayashi, M. Conservation of the Keap1-Nrf2 system: an evolutionary journey through stressful space and time. Molecules 22, E436 (2017).

    Article  CAS  PubMed  Google Scholar 

  112. Shin, C.S. et al. The glutamate/cystine xCT antiporter antagonizes glutamine metabolism and reduces nutrient flexibility. Nat. Commun. 8, 15074 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Liu, D. S. et al. Inhibiting the system xC-/glutathione axis selectively targets cancers with mutant-p53 accumulation. Nat. Commun. 8, 14844 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Garritano, S., Inga, A., Gemignani, F. & Landi, S. More targets, more pathways and more clues for mutant p53. Oncogenesis 2, e54 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Suzuki, S. et al. Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen species. Proc. Natl Acad. Sci. USA 107, 7461–7466 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Khoo, K. H., Verma, C. S. & Lane, D. P. Drugging the p53 pathway: understanding the route to clinical efficacy. Nat. Rev. Drug Discov. 13, 217–236 (2014).

    Article  CAS  PubMed  Google Scholar 

  117. Izetti, P. et al. PRIMA-1, a mutant p53 reactivator, induces apoptosis and enhances chemotherapeutic cytotoxicity in pancreatic cancer cell lines. Invest. New Drugs 32, 783–794 (2014).

    Article  CAS  PubMed  Google Scholar 

  118. Cui, B. et al. PRIMA-1, a mutant p53 reactivator, restores the sensitivity of TP53 mutant-type thyroid cancer cells to the histone methylation inhibitor 3-deazaneplanocin A. J Clin Endocrinol Metab. 99, E962–E970 (2014).

    Article  CAS  PubMed  Google Scholar 

  119. Cheng, L. L. et al. TP53 genomic status regulates sensitivity of gastric cancer cells to the histone methylation inhibitor 3-deazaneplanocin A (DZNep). Clin. Cancer Res. 18, 4201–4212 (2012).

    Article  CAS  PubMed  Google Scholar 

  120. Zhou, J. et al. The histone methyltransferase inhibitor, DZNep, up-regulates TXNIP, increases ROS production, and targets leukemia cells in AML. Blood 118, 2830–2839 (2011).

    Article  PubMed  Google Scholar 

  121. Jung, H. et al. TXNIP maintains the hematopoietic cell pool by switching the function of p53 under oxidative stress. Cell Metab. 18, 75–85 (2013).

    Article  CAS  PubMed  Google Scholar 

  122. Sosman, J. A. et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N. Engl. J. Med. 366, 707–714 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Trunzer, K. et al. Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma. J. Clin. Oncol. 31, 1767–1774 (2013).

    Article  CAS  PubMed  Google Scholar 

  124. Paraiso, K. H. et al. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res. 71, 2750–2760 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Su, F. et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N. Engl. J. Med. 366, 207–215 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  126. Krayem, M. et al. p53 reactivation by PRIMA-1(Met) (APR-246) sensitises (V600E/K)BRAF melanoma to vemurafenib. Eur. J. Cancer 55, 98–110 (2016).

    Article  CAS  PubMed  Google Scholar 

  127. Bao, W. et al. 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 (2011).

    Article  CAS  PubMed  Google Scholar 

  128. Deben, C. et al. APR-246 (PRIMA-1(MET)) strongly synergizes with AZD2281 (olaparib) induced PARP inhibition to induce apoptosis in non-small cell lung cancer cell lines. Cancer Lett. 375, 313–322 (2016).

    Article  CAS  PubMed  Google Scholar 

  129. Ali, D. et al. Anti-leukaemic effects induced by APR-246 are dependent on induction of oxidative stress and the NFE2L2/HMOX1 axis that can be targeted by PI3K and mTOR inhibitors in acute myeloid leukaemia cells. Br. J. Haematol. 174, 117–126 (2016).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  131. Bordeira-Carrico, R., Pego, A. P., Santos, M. & Oliveira, C. Cancer syndromes and therapy by stop-codon readthrough. Trends Mol. Med. 18, 667–678 (2012).

    Article  CAS  PubMed  Google Scholar 

  132. Hwang, J. & Kim, Y. K. When a ribosome encounters a premature termination codon. BMB Rep. 46, 9–16 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Lykke-Andersen, S. & Jensen, T. H. Nonsense-mediated mRNA decay: an intricate machinery that shapes transcriptomes. Nat. Rev. Mol. Cell Biol. 16, 665–677 (2015).

    Article  CAS  PubMed  Google Scholar 

  134. Chauvin, C. et al. Involvement of human release factors eRF3a and eRF3b in translation termination and regulation of the termination complex formation. Mol. Cell. Biol. 25, 5801–5811 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Welch, E. M. et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature 447, 87–91 (2007).

    Article  CAS  PubMed  Google Scholar 

  136. Auld, D. S. et al. Molecular basis for the high-affinity binding and stabilization of firefly luciferase by PTC124. Proc. Natl Acad. Sci. USA 107, 4878–4883 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Zainal Abidin, N., Haq, I. J., Gardner, A. I. & Brodlie, M. Ataluren in cystic fibrosis: development, clinical studies and where are we now? Expert Opin. Pharmacother. 18, 1363–1371 (2017).

    Article  CAS  PubMed  Google Scholar 

  138. McDonald, C. M. et al. Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet, 31611–31612 (2017).

  139. Floquet, C., Deforges, J., Rousset, J. P. & Bidou, L. Rescue of non-sense mutated p53 tumor suppressor gene by aminoglycosides. Nucleic Acids Res. 39, 3350–3362 (2011). This is the first study showing that aminoglycoside antibiotics can induce translational readthrough of nonsense TP53 mutations and expression of full-length p53 protein.

    Article  CAS  PubMed  Google Scholar 

  140. Bidou, L., Bugaud, O., Belakhov, V., Baasov, T. & Namy, O. Characterization of new-generation aminoglycoside promoting premature termination codon readthrough in cancer cells. RNA Biol. 14, 378–388 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Baradaran-Heravi, A. et al. Gentamicin B1 is a minor gentamicin component with major nonsense mutation suppression activity. Proc. Natl Acad. Sci. USA 114, 3479–3484 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Manuvakhova, M., Keeling, K. & Bedwell, D. M. Aminoglycoside antibiotics mediate context-dependent suppression of termination codons in a mammalian translation system. RNA 6, 1044–1055 (2000).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Amrani, N. et al. A faux 3′-UTR promotes aberrant termination and triggers nonsense-mediated mRNA decay. Nature 432, 112–118 (2004).

    Article  CAS  PubMed  Google Scholar 

  144. Mingeot-Leclercq, M. P. & Tulkens, P. M. Aminoglycosides: nephrotoxicity. Antimicrob. Agents Chemother. 43, 1003–1012 (1999).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Hutchin, T. & Cortopassi, G. Proposed molecular and cellular mechanism for aminoglycoside ototoxicity. Antimicrob. Agents Chemother. 38, 2517–2520 (1994).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Martin, L. et al. Identification and characterization of small molecules that inhibit nonsense mediated RNA decay and suppress nonsense p53 mutations. Cancer Res. 74, 3104–3113 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Baradaran-Heravi, A. et al. Novel small molecules potentiate premature termination codon readthrough by aminoglycosides. Nucleic Acids Res. 44, 6583–6598 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Tessoulin, B. et al. PRIMA-1Met induces myeloma cell death independent of p53 by impairing the GSH/ROS balance. Blood 124, 1626–1636 (2014).

    Article  CAS  PubMed  Google Scholar 

  149. Gorrini, C., Harris, I. S. & Mak, T. W. Modulation of oxidative stress as an anticancer strategy. Nat. Rev. Drug Discov. 12, 931–947 (2013).

    Article  CAS  PubMed  Google Scholar 

  150. Lambert, J. M., Moshfegh, A., Hainaut, P., Wiman, K. G. & Bykov, V. J. Mutant p53 reactivation by PRIMA-1(MET) induces multiple signaling pathways converging on apoptosis. Oncogene 29, 1329–1338 (2010).

    Article  CAS  PubMed  Google Scholar 

  151. Ali, D. et al. APR-246 exhibits anti-leukemic activity and synergism with conventional chemotherapeutic drugs in acute myeloid leukemia cells. Eur. J. Haematol. 86, 206–215 (2011).

    Article  CAS  PubMed  Google Scholar 

  152. Aryee, D. N. et al. Variability in functional p53 reactivation by PRIMA-1(Met)/APR-246 in Ewing sarcoma. Br. J. Cancer 109, 2696–2704 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Grellety, T. et al. PRIMA-1(MET) induces death in soft-tissue sarcomas cell independent of p53. BMC Cancer 15, 684 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Sobhani, M., Abdi, J., Manujendra, S. N., Chen, C. & Chang, H. PRIMA-1Met induces apoptosis in Waldenstrom's macroglobulinemia cells independent of p53. Cancer Biol. Ther. 16, 799–806 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  155. Lu, T. et al. PRIMA-1Met suppresses colorectal cancer independent of p53 by targeting MEK. Oncotarget 7, 83017–83030 (2016).

    PubMed  PubMed Central  Google Scholar 

  156. Blanden, A. R., Yu, X., Loh, S. N., Levine, A. J. & Carpizo, D. R. Reactivating mutant p53 using small molecules as zinc metallochaperones: awakening a sleeping giant in cancer. Drug Discov. Today 20, 1391–1397 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. Yu, X. et al. Thiosemicarbazones functioning as zinc metallochaperones to reactivate mutant p53. Mol. Pharmacol. 91, 567–575 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  158. Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012).

    Article  PubMed  Google Scholar 

  159. Zehir, A. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat. Med. 23, 703–713 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  160. Berman, H. M. et al. The protein data bank. Nucleic Acids Res. 28, 235–242 (2000).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  161. Kitayner, M. et al. Structural basis of DNA recognition by p53 tetramers. Mol. Cell 22, 741–753 (2006).

    Article  CAS  PubMed  Google Scholar 

  162. Hug, N., Longman, D. & Caceres, J. F. Mechanism and regulation of the nonsense-mediated decay pathway. Nucleic Acids Res. 44, 1483–1495 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

K.G.W. is supported by grants from the Swedish Cancer Foundation (Cancerfonden), the Swedish Medical Research Council (VR), the Swedish Childhood Cancer Foundation (Barncancerfonden), Radiumhemmets Forskningsfonder, Karolinska Institutet, the Wallenberg Foundation (KAW), the European Research Council (ERC) and Aprea Therapeutics AB. J.B. is supported by Svenska Sällskapet för Medicinsk Forskning (SSMF). The authors thank L. Abrahmsen, R. Tell and M. von Euler, Aprea Therapeutics AB, for valuable comments on the manuscript.

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Authors and Affiliations

  1. Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska (CCK), Stockholm, SE-171 77, Sweden

    Vladimir J. N. Bykov, Sofi E. Eriksson, Julie Bianchi & Klas G. Wiman

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  1. Vladimir J. N. Bykov
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  2. Sofi E. Eriksson
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K.G.W., V.J.N.B., S.E.E. and J.B. researched data for the article, made substantial contributions to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission. K.G.W. was responsible for communication with the editor and preparation of the final version of the manuscript.

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Correspondence to Klas G. Wiman.

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Competing interests

K.G.W. and V.J.N.B. are cofounders and shareholders of Aprea Therapeutics AB, a company that develops p53-based cancer therapy, including APR-246. K.G.W. is a member of its Clinical Advisory Board. Research in the K.G.W. laboratory has financial support from Aprea Therapeutics AB. K.G.W. has received a salary from Aprea Therapeutics AB. The other authors declare no competing interests.

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DATABASES

RCSB Protein Data Bank

FURTHER INFORMATION

TP53 website

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Glossary

Ferroptosis

A mode of regulated cell death that requires iron and that depends on lipid peroxidation.

Missense mutations

Mutations that give rise to an amino acid substitution in the protein.

Nonsense mutations

Mutations that create a premature termination codon and cause expression of a truncated protein.

Translational readthrough

A process in which the ribosome continues translation through a premature termination codon in an mRNA, leading to synthesis of full-length protein.

Law of mass action

A law that states that the rate of a chemical reaction is directly proportional to the product of the masses or concentrations of the reactants.

Michael acceptors

Organic molecules with an unsaturated carbon–carbon double bond coupled to an electron-withdrawing group.

Michael addition

The conjugate addition of a Michael acceptor to a nucleophile.

Pegylated doxorubicin

A formulation of the chemotherapeutic drug doxorubicin in which the drug is packed in liposomes, allowing improved longevity and drug delivery to tumour tissue.

Response Evaluation Criteria in Solid Tumours 1.1

(RECIST1.1). Defined rules for assessment of the treatment response of patients with cancer. RECIST1.1 differs from RECIST with regard to several criteria, including the number of lesions to be assessed and the assessment of pathological lymph nodes.

Gynecologic Cancer InterGroup

(GCIG). An organization with the aim of promoting high-quality clinical trials in order to improve outcomes for patients with gynaecological cancer.

Nucleophilic aromatic substitution

A substitution reaction in which a nucleophile replaces a leaving aromatic group.

Imino group

A functional group containing a carbon–nitrogen double bond.

Nonsense-mediated mRNA decay

(NMD). A pathway that selectively degrades mRNAs with premature termination codons.

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Bykov, V., Eriksson, S., Bianchi, J. et al. Targeting mutant p53 for efficient cancer therapy. Nat Rev Cancer 18, 89–102 (2018). https://doi.org/10.1038/nrc.2017.109

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