Therapeutic targeting of TP53 nonsense mutations in cancer
Keywords:
TP53, nonsense mutations, translational readthrough, cancer therapy
Abstract
Mutations in the TP53 tumor suppressor gene occur with high prevalence in a wide range of human tumors. A significant fraction of these mutations (around 10%) are nonsense mutations, creating a premature termination codon (PTC) that leads to the expression of truncated inactive p53 protein. Induction of translational readthrough across a PTC in nonsense mutant TP53 allows the production of full-length protein and potentially restoration of normal p53 function. Aminoglycoside antibiotics and a number of novel compounds have been shown to induce full-length p53 in tumor cells carrying various TP53 nonsense mutations. Full-length p53 protein generated by translational readthrough retains the capacity to transactivate p53 target genes and trigger tumor cell death. These findings raise hopes for efficient therapy of TP53 nonsense mutant tumors in the future.
Downloads
Download data is not yet available.
References
1. Mort M, Ivanov D, Cooper DN, Chuzhanova NA. A meta-analysis of nonsense mutations causing human genetic disease. Hum Mutat. 2008;29:1037–47. doi: 10.1002/humu.20763
2. Keeling KM, Xue X, Gunn G, Bedwell DM. Therapeutics based on stop codon readthrough. Annu Rev Genomics Hum Genet. 2014;15:371–94. doi: 10.1146/annurev-genom-091212-153527
3. Sharma J, Keeling KM, Rowe SM. Pharmacological approaches for targeting cystic fibrosis nonsense mutations. Eur J Med Chem. 2020;200:112436. doi: 10.1016/j.ejmech.2020.112436
4. Bez Batti Angulski A, Hosny N, Cohen H, Martin AA, Hahn D, Bauer J, et al. Duchenne muscular dystrophy: disease mechanism and therapeutic strategies. Front Physiol. 2023;14:1183101. doi: 10.3389/fphys.2023.1183101
5. Keinath MC, Prior DE, Prior TW. Spinal muscular atrophy: mutations, testing, and clinical relevance. Appl Clin Genet. 2021;14:11–25. doi: 10.2147/TACG.S239603
6. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz Jr, LA, Kinzler KW. Cancer genome landscapes. Science. 2013;339:1546–58. doi: 10.1126/science.1235122
7. Tate JG, Bamford S, Jubb HC, Sondka Z, Beare DM, Bindal N, et al. COSMIC: the catalogue of somatic mutations in cancer. Nucleic Acids Res. 2019;47:D941–7. doi: 10.1093/nar/gky1015
8. Linde L, Kerem B. Introducing sense into nonsense in treatments of human genetic diseases. Trends Genet. 2008;24:552–63. doi: 10.1016/j.tig.2008.08.010
9. Singh A, Ursic D, Davies J. Phenotypic suppression and misreading Saccharomyces cerevisiae. Nature. 1979;277:146–8. doi: 10.1038/277146a0
10. Palmer E, Wilhelm JM, Sherman F. Phenotypic suppression of nonsense mutants in yeast by aminoglycoside antibiotics. Nature. 1979;277:148–50. doi: 10.1038/277148a0
11. Burke JF, Mogg AE. Suppression of a nonsense mutation in mammalian cells in vivo by the aminoglycoside antibiotics G-418 and paromomycin. Nucleic Acids Res. 1985;13:6265–72. doi: 10.1093/nar/13.17.6265
12. Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature. 2007;447:87–91. doi: 10.1038/nature05756
13. Du M, Liu X, Welch EM, Hirawat S, Peltz SW, Bedwell DM. PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model. Proc Natl Acad Sci U S A. 2008;105:2064–9. doi: 10.1073/pnas.0711795105
14. Sharma J, Du M, Wong E, Mutyam V, Li Y, Chen J, et al. A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion. Nat Commun. 2021;12:4358. doi: 10.1038/s41467-021-24575-x
15. Albers S, Allen EC, Bharti N, Davyt M, Joshi D, Perez-Garcia CG, et al. Engineered tRNAs suppress nonsense mutations in cells and in vivo. Nature. 2023;618:842–8. doi: 10.1038/s41586-023-06133-1
16. Keeling KM and Bedwell DM. Clinically relevant aminoglycosides can suppress disease-associated premature stop mutations in the IDUA and P53 cDNAs in a mammalian translation system. J Mol Med (Berl). 2002;80:367–76. doi: 10.1007/s00109-001-0317-z
17. Floquet C, Deforges J, Rousset JP, Bidou L. Rescue of non-sense mutated p53 tumor suppressor gene by aminoglycosides. Nucleic Acids Res. 2011;39:3350–62. doi: 10.1093/nar/gkq1277
18. Friesen WJ, Johnson B, Sierra J, Zhuo J, Vazirani P, Xue X, et al. The minor gentamicin complex component, X2, is a potent premature stop codon readthrough molecule with therapeutic potential. PLoS One. 2018;13:e0206158. doi: 10.1371/journal.pone.0206158
19. Kandasamy J, Atia-Glikin D, Shulman E, Shapira K, Shavit M, Belakhov V, et al. Increased selectivity toward cytoplasmic versus mitochondrial ribosome confers improved efficiency of synthetic aminoglycosides in fixing damaged genes: a strategy for treatment of genetic diseases caused by nonsense mutations. J Med Chem. 2012;55:10630–43. doi: 10.1021/jm3012992
20. Crawford DK, Alroy I, Sharpe N, Goddeeris MM, Williams G. ELX-02 Generates protein via premature stop codon read-through without inducing native stop codon read-through proteins. J Pharmacol Exp Ther. 2020;374:264–72. doi: 10.1124/jpet.120.265595
21. Friesen WJ, Trotta CR, Tomizawa Y, Zhuo J, Johnson B, Sierra J, et al. The nucleoside analog clitocine is a potent and efficacious readthrough agent. RNA. 2017;23:567–77. doi: 10.1261/rna.060236.116
22. Trzaska C, Amand S, Bailly C, Leroy C, Marchand V, Duvernois-Berthet E, et al. 2,6-Diaminopurine as a highly potent corrector of UGA nonsense mutations. Nat Commun. 2020;11:1509. doi: 10.1038/s41467-020-15140-z
23. Chauvin C, Salhi S, Le Goff C, Viranaicken W, Diop D, Jean-Jean O. Involvement of human release factors eRF3a and eRF3b in translation termination and regulation of the termination complex formation. Mol Cell Biol. 2005;25:5801–11. doi: 10.1128/MCB.25.14.5801-5811.2005
24. Matyskiela ME, Lu G, Ito T, Pagarigan B, Lu CC, Miller K, et al. A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase. Nature. 2016;535:252–7. doi: 10.1038/nature18611
25. Lopez-Girona A, Lu G, Rychak E, Mendy D, Lu CC, Rappley I, et al. CC-90009, a novel cereblon E3 ligase modulator, targets GSPT1 for degradation to induce potent tumoricidal activity against acute myeloid leukemia (AML). Blood. 2019;134:2703. doi: 10.1182/blood-2019-127892
26. Baradaran-Heravi A, Balgi AD, Hosseini-Farahabadi S, Choi K, Has C, Roberge M. Effect of small molecule eRF3 degraders on premature termination codon readthrough. Nucleic Acids Res. 2021;49:3692–708. doi: 10.1093/nar/gkab194
27. Bidou L, Bugaud O, Merer G, Coupet M, Hatin I, Chirkin E, et al. 2-Guanidino-quinazoline promotes the readthrough of nonsense mutations underlying human genetic diseases. Proc Natl Acad Sci U S A. 2022;119:e2122004119. doi: 10.1073/pnas.2122004119
28. Palomar-Siles M, Heldin A, Zhang M, Strandgren C, Yurevych V, van Dinter JT, et al. Translational readthrough of nonsense mutant TP53 by mRNA incorporation of 5-Fluorouridine. Cell Death Dis. 2022;13:997. doi: 10.1038/s41419-022-05431-2
29. Champe SP, Benzer S. Reversal of mutant phenotypes by 5-fluorouracil: an approach to nucleotide sequences in messenger-RNA. Proc Natl Acad Sci U S A. 1962;48:532–46. doi: 10.1073/pnas.48.4.532
30. Heldin A, Cancer M, Palomar-Siles M, Ohlin S, Zhang M, Sun-Zhang A, et al. Novel compounds that synergize with aminoglycoside G418 or eRF3 degraders for translational readthrough of nonsense mutant TP53 and PTEN. RNA Biol. 2023;20:368–83. doi: 10.1080/15476286.2023.2222250
31. Fodde R, Smits R, Clevers H. APC, signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer. 2001;1:55–67. doi: 10.1038/35094067
32. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502:333–9. doi: 10.1038/nature12634
33. Beroud C, Soussi T. APC gene: database of germline and somatic mutations in human tumors and cell lines. Nucleic Acids Res. 1996;24:121–4. doi: 10.1093/nar/24.1.121
34. Zilberberg A, Lahav L, Rosin-Arbesfeld R. Restoration of APC gene function in colorectal cancer cells by aminoglycoside- and macrolide-induced read-through of premature termination codons. Gut. 2010;59:496–507. doi: 10.1136/gut.2008.169805
35. Lee YR, Chen M, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nat Rev Mol Cell Biol. 2018;19:547–62. doi: 10.1038/s41580-018-0015-0
36. Luna S, Torices L, Mingo J, Amo L, Rodriguez-Escudero I, Ruiz-Ibarlucea P, et al. A global analysis of the reconstitution of PTEN function by translational readthrough of PTEN pathogenic premature termination codons. Hum Mutat. 2021;42:551–66. doi: 10.1002/humu.24186
37. Weinberg RA. The retinoblastoma protein and cell cycle control. Cell. 1995;81:323–30. doi: 10.1016/0092-8674(95)90385-2
38. Palomar-Siles M, Yurevych V, Bykov VJN, Wiman KG. Pharmacological induction of translational readthrough of nonsense mutations in the retinoblastoma (RB1) gene. PLoS One. 2023;18:e0292468. doi: 10.1371/journal.pone.0292468
39. Zhang M, Heldin A, Palomar-Siles M, Ohlin S, Bykov VJN, Wiman KG. Synergistic rescue of nonsense mutant tumor suppressor p53 by combination treatment with aminoglycosides and Mdm2 inhibitors. Front Oncol. 2018;7:323. doi: 10.3389/fonc.2017.00323
2. Keeling KM, Xue X, Gunn G, Bedwell DM. Therapeutics based on stop codon readthrough. Annu Rev Genomics Hum Genet. 2014;15:371–94. doi: 10.1146/annurev-genom-091212-153527
3. Sharma J, Keeling KM, Rowe SM. Pharmacological approaches for targeting cystic fibrosis nonsense mutations. Eur J Med Chem. 2020;200:112436. doi: 10.1016/j.ejmech.2020.112436
4. Bez Batti Angulski A, Hosny N, Cohen H, Martin AA, Hahn D, Bauer J, et al. Duchenne muscular dystrophy: disease mechanism and therapeutic strategies. Front Physiol. 2023;14:1183101. doi: 10.3389/fphys.2023.1183101
5. Keinath MC, Prior DE, Prior TW. Spinal muscular atrophy: mutations, testing, and clinical relevance. Appl Clin Genet. 2021;14:11–25. doi: 10.2147/TACG.S239603
6. Vogelstein B, Papadopoulos N, Velculescu VE, Zhou S, Diaz Jr, LA, Kinzler KW. Cancer genome landscapes. Science. 2013;339:1546–58. doi: 10.1126/science.1235122
7. Tate JG, Bamford S, Jubb HC, Sondka Z, Beare DM, Bindal N, et al. COSMIC: the catalogue of somatic mutations in cancer. Nucleic Acids Res. 2019;47:D941–7. doi: 10.1093/nar/gky1015
8. Linde L, Kerem B. Introducing sense into nonsense in treatments of human genetic diseases. Trends Genet. 2008;24:552–63. doi: 10.1016/j.tig.2008.08.010
9. Singh A, Ursic D, Davies J. Phenotypic suppression and misreading Saccharomyces cerevisiae. Nature. 1979;277:146–8. doi: 10.1038/277146a0
10. Palmer E, Wilhelm JM, Sherman F. Phenotypic suppression of nonsense mutants in yeast by aminoglycoside antibiotics. Nature. 1979;277:148–50. doi: 10.1038/277148a0
11. Burke JF, Mogg AE. Suppression of a nonsense mutation in mammalian cells in vivo by the aminoglycoside antibiotics G-418 and paromomycin. Nucleic Acids Res. 1985;13:6265–72. doi: 10.1093/nar/13.17.6265
12. Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature. 2007;447:87–91. doi: 10.1038/nature05756
13. Du M, Liu X, Welch EM, Hirawat S, Peltz SW, Bedwell DM. PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model. Proc Natl Acad Sci U S A. 2008;105:2064–9. doi: 10.1073/pnas.0711795105
14. Sharma J, Du M, Wong E, Mutyam V, Li Y, Chen J, et al. A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion. Nat Commun. 2021;12:4358. doi: 10.1038/s41467-021-24575-x
15. Albers S, Allen EC, Bharti N, Davyt M, Joshi D, Perez-Garcia CG, et al. Engineered tRNAs suppress nonsense mutations in cells and in vivo. Nature. 2023;618:842–8. doi: 10.1038/s41586-023-06133-1
16. Keeling KM and Bedwell DM. Clinically relevant aminoglycosides can suppress disease-associated premature stop mutations in the IDUA and P53 cDNAs in a mammalian translation system. J Mol Med (Berl). 2002;80:367–76. doi: 10.1007/s00109-001-0317-z
17. Floquet C, Deforges J, Rousset JP, Bidou L. Rescue of non-sense mutated p53 tumor suppressor gene by aminoglycosides. Nucleic Acids Res. 2011;39:3350–62. doi: 10.1093/nar/gkq1277
18. Friesen WJ, Johnson B, Sierra J, Zhuo J, Vazirani P, Xue X, et al. The minor gentamicin complex component, X2, is a potent premature stop codon readthrough molecule with therapeutic potential. PLoS One. 2018;13:e0206158. doi: 10.1371/journal.pone.0206158
19. Kandasamy J, Atia-Glikin D, Shulman E, Shapira K, Shavit M, Belakhov V, et al. Increased selectivity toward cytoplasmic versus mitochondrial ribosome confers improved efficiency of synthetic aminoglycosides in fixing damaged genes: a strategy for treatment of genetic diseases caused by nonsense mutations. J Med Chem. 2012;55:10630–43. doi: 10.1021/jm3012992
20. Crawford DK, Alroy I, Sharpe N, Goddeeris MM, Williams G. ELX-02 Generates protein via premature stop codon read-through without inducing native stop codon read-through proteins. J Pharmacol Exp Ther. 2020;374:264–72. doi: 10.1124/jpet.120.265595
21. Friesen WJ, Trotta CR, Tomizawa Y, Zhuo J, Johnson B, Sierra J, et al. The nucleoside analog clitocine is a potent and efficacious readthrough agent. RNA. 2017;23:567–77. doi: 10.1261/rna.060236.116
22. Trzaska C, Amand S, Bailly C, Leroy C, Marchand V, Duvernois-Berthet E, et al. 2,6-Diaminopurine as a highly potent corrector of UGA nonsense mutations. Nat Commun. 2020;11:1509. doi: 10.1038/s41467-020-15140-z
23. Chauvin C, Salhi S, Le Goff C, Viranaicken W, Diop D, Jean-Jean O. Involvement of human release factors eRF3a and eRF3b in translation termination and regulation of the termination complex formation. Mol Cell Biol. 2005;25:5801–11. doi: 10.1128/MCB.25.14.5801-5811.2005
24. Matyskiela ME, Lu G, Ito T, Pagarigan B, Lu CC, Miller K, et al. A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase. Nature. 2016;535:252–7. doi: 10.1038/nature18611
25. Lopez-Girona A, Lu G, Rychak E, Mendy D, Lu CC, Rappley I, et al. CC-90009, a novel cereblon E3 ligase modulator, targets GSPT1 for degradation to induce potent tumoricidal activity against acute myeloid leukemia (AML). Blood. 2019;134:2703. doi: 10.1182/blood-2019-127892
26. Baradaran-Heravi A, Balgi AD, Hosseini-Farahabadi S, Choi K, Has C, Roberge M. Effect of small molecule eRF3 degraders on premature termination codon readthrough. Nucleic Acids Res. 2021;49:3692–708. doi: 10.1093/nar/gkab194
27. Bidou L, Bugaud O, Merer G, Coupet M, Hatin I, Chirkin E, et al. 2-Guanidino-quinazoline promotes the readthrough of nonsense mutations underlying human genetic diseases. Proc Natl Acad Sci U S A. 2022;119:e2122004119. doi: 10.1073/pnas.2122004119
28. Palomar-Siles M, Heldin A, Zhang M, Strandgren C, Yurevych V, van Dinter JT, et al. Translational readthrough of nonsense mutant TP53 by mRNA incorporation of 5-Fluorouridine. Cell Death Dis. 2022;13:997. doi: 10.1038/s41419-022-05431-2
29. Champe SP, Benzer S. Reversal of mutant phenotypes by 5-fluorouracil: an approach to nucleotide sequences in messenger-RNA. Proc Natl Acad Sci U S A. 1962;48:532–46. doi: 10.1073/pnas.48.4.532
30. Heldin A, Cancer M, Palomar-Siles M, Ohlin S, Zhang M, Sun-Zhang A, et al. Novel compounds that synergize with aminoglycoside G418 or eRF3 degraders for translational readthrough of nonsense mutant TP53 and PTEN. RNA Biol. 2023;20:368–83. doi: 10.1080/15476286.2023.2222250
31. Fodde R, Smits R, Clevers H. APC, signal transduction and genetic instability in colorectal cancer. Nat Rev Cancer. 2001;1:55–67. doi: 10.1038/35094067
32. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature. 2013;502:333–9. doi: 10.1038/nature12634
33. Beroud C, Soussi T. APC gene: database of germline and somatic mutations in human tumors and cell lines. Nucleic Acids Res. 1996;24:121–4. doi: 10.1093/nar/24.1.121
34. Zilberberg A, Lahav L, Rosin-Arbesfeld R. Restoration of APC gene function in colorectal cancer cells by aminoglycoside- and macrolide-induced read-through of premature termination codons. Gut. 2010;59:496–507. doi: 10.1136/gut.2008.169805
35. Lee YR, Chen M, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor: new modes and prospects. Nat Rev Mol Cell Biol. 2018;19:547–62. doi: 10.1038/s41580-018-0015-0
36. Luna S, Torices L, Mingo J, Amo L, Rodriguez-Escudero I, Ruiz-Ibarlucea P, et al. A global analysis of the reconstitution of PTEN function by translational readthrough of PTEN pathogenic premature termination codons. Hum Mutat. 2021;42:551–66. doi: 10.1002/humu.24186
37. Weinberg RA. The retinoblastoma protein and cell cycle control. Cell. 1995;81:323–30. doi: 10.1016/0092-8674(95)90385-2
38. Palomar-Siles M, Yurevych V, Bykov VJN, Wiman KG. Pharmacological induction of translational readthrough of nonsense mutations in the retinoblastoma (RB1) gene. PLoS One. 2023;18:e0292468. doi: 10.1371/journal.pone.0292468
39. Zhang M, Heldin A, Palomar-Siles M, Ohlin S, Bykov VJN, Wiman KG. Synergistic rescue of nonsense mutant tumor suppressor p53 by combination treatment with aminoglycosides and Mdm2 inhibitors. Front Oncol. 2018;7:323. doi: 10.3389/fonc.2017.00323
Published
2024-05-27
How to Cite
Strandgren C., & Wiman K. G. (2024). Therapeutic targeting of TP53 nonsense mutations in cancer. Upsala Journal of Medical Sciences, 129(S1), e10719. https://doi.org/10.48101/ujms.v129.10719
Issue
Section
Review Articles
This work is licensed under a Creative Commons Attribution 4.0 International License.
Authors retain copyright of their work, with first publication rights granted to Upsala Medical Society. Read the full Copyright- and Licensing Statement.
