Pharmacological targeting of nonsense mutant TP53 and PTEN in cancer
Author: Heldin, Angelos
Date: 2023-10-20
Location: Cancer center Karolinska, lecture hall R8:00, Karolinska University Hospital, Solna
Time: 09.30
Department: Inst för onkologi-patologi / Dept of Oncology-Pathology
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Thesis (895.1Kb)
Abstract
The TP53 tumor suppressor gene encodes p53 and is inactivated by mutations in
around half of all human tumors. Approximately 11% of TP53 mutations are
nonsense mutations, resulting in the premature termination of translation and the
production of truncated and non-functional p53 proteins. Aminoglycosides such
as G418 are known to induce translational readthrough, a process in which the
ribosome overcomes the stop signal introduced by a nonsense mutation and
translates full-length protein. However, the clinical use of aminoglycosides is
restricted due to severe side effects. We have demonstrated that combination
treatments with proteasome inhibitors or compounds that disrupt the binding of
p53 to the ubiquitin ligase MDM2 can synergistically enhance the levels of fulllength
p53, improving the efficacy of readthrough compared to aminoglycosides
alone. These combinations were proven to produce at least partially active fulllength
p53, as shown by the suppression of cell growth and the induction of cell
death. In parallel, chemical library screenings led to the discovery of two novel
compounds, C47 and C61, showing readthrough activity and synergizing with G418
and eRF3 degraders CC-885 and CC-90009, respectively. Remarkably, C47 also
exhibit readthrough activity for nonsense mutant phosphatase and tensin
homolog (PTEN), expanding the scope for targeted cancer therapies. Furthermore,
we have identified the 5-fluorouracil (5-FU) metabolite 5-Fluorouridine (FUr) as a
potent readthrough-inducing compounds capable restoring full-length p53
expression in cells harboring nonsense mutant TP53. In vivo studies further
substantiated the capability of FUr to reinstate full-length p53 expression in
human tumor xenografts with TP53 R213X nonsense mutations. Finally, the first
Trp53 R210X nonsense mutant knock-in mouse model has been generated. R210X
corresponds to human TP53 R213X. Observations on tumor development, lifespan
and other phenotypic traits in these mice provide valuable insights into the impact
of TP53 nonsense mutation in a multi-organ system. These results also provide a
platform for the preclinical evaluation of novel therapeutic strategies for targeting
nonsense mutant TP53.
In summary, these findings offer a multi-faceted approach towards understanding TP53 nonsense mutations and advancing targeted cancer therapy through pharmacological induction of translational readthrough. The discovery of novel readthrough inducing compounds, the application of combination therapy in translational readthrough, the discovery of a novel therapeutic application for 5- FU and its metabolite FUr, as well as the generation of a novel animal model collectively set the stage for the further development of personalized treatments for patients with tumors harboring nonsense mutant TP53.
In summary, these findings offer a multi-faceted approach towards understanding TP53 nonsense mutations and advancing targeted cancer therapy through pharmacological induction of translational readthrough. The discovery of novel readthrough inducing compounds, the application of combination therapy in translational readthrough, the discovery of a novel therapeutic application for 5- FU and its metabolite FUr, as well as the generation of a novel animal model collectively set the stage for the further development of personalized treatments for patients with tumors harboring nonsense mutant TP53.
List of papers:
I. Synergistic rescue of nonsense mutant tumor suppressor p53 by combination treatment with aminoglycosides and Mdm2 inhibitors. Meiqiongzi Zhang*, Angelos Heldin*, Mireia Palomar-Siles, Susanne Öhlin, Vladimir J. N. Bykov and Klas G. Wiman. Frontiers in Oncology. (2018), 7:323. *Authors contributed equally.
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II. Novel compounds that synergize with aminoglycoside G418 or eRF3 degraders for translational readthrough of nonsense mutant TP53 and PTEN. Angelos Heldin, Matko Cancer*, Mireia Palomar-Siles*, Meiqiongzi Zhang, Susanne Öhlin, Anna Mariani, Alexander Sun-Zhang, Jianping Liu, Vladimir J.N. Bykov and Klas G. Wiman. RNA Biology. (2023), 20:368. *Authors contributed equally.
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III. Translational readthrough of nonsense mutant TP53 by mRNA incorporation of 5-Fluorouridine. Mireia Palomar-Siles, Angelos Heldin, Meiqiongzi Zhang, Charlotte Strandgren, Viktor Yurevych, Jip T. van Dinter, Sem A. G. Engels, Damon A. Hofman, Susanne Öhlin, Birthe Meineke, Vladimir J. N. Bykov, Sebastiaan van Heesch and Klas G. Wiman. Cell Death & Disease. (2022), 13:997.
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IV. A novel tumor-prone mouse model harboring the Trp53R210X nonsense mutation. Charlotte Strandgren, Angelos Heldin, Susanne Öhlin and Klas G. Wiman. [Manuscript]
I. Synergistic rescue of nonsense mutant tumor suppressor p53 by combination treatment with aminoglycosides and Mdm2 inhibitors. Meiqiongzi Zhang*, Angelos Heldin*, Mireia Palomar-Siles, Susanne Öhlin, Vladimir J. N. Bykov and Klas G. Wiman. Frontiers in Oncology. (2018), 7:323. *Authors contributed equally.
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II. Novel compounds that synergize with aminoglycoside G418 or eRF3 degraders for translational readthrough of nonsense mutant TP53 and PTEN. Angelos Heldin, Matko Cancer*, Mireia Palomar-Siles*, Meiqiongzi Zhang, Susanne Öhlin, Anna Mariani, Alexander Sun-Zhang, Jianping Liu, Vladimir J.N. Bykov and Klas G. Wiman. RNA Biology. (2023), 20:368. *Authors contributed equally.
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III. Translational readthrough of nonsense mutant TP53 by mRNA incorporation of 5-Fluorouridine. Mireia Palomar-Siles, Angelos Heldin, Meiqiongzi Zhang, Charlotte Strandgren, Viktor Yurevych, Jip T. van Dinter, Sem A. G. Engels, Damon A. Hofman, Susanne Öhlin, Birthe Meineke, Vladimir J. N. Bykov, Sebastiaan van Heesch and Klas G. Wiman. Cell Death & Disease. (2022), 13:997.
Fulltext (DOI)
Pubmed
View record in Web of Science®
IV. A novel tumor-prone mouse model harboring the Trp53R210X nonsense mutation. Charlotte Strandgren, Angelos Heldin, Susanne Öhlin and Klas G. Wiman. [Manuscript]
Institution: Karolinska Institutet
Supervisor: Wiman, Klas
Co-supervisor: Bykov, Vladimir
Issue date: 2023-09-15
Rights:
Publication year: 2023
ISBN: 978-91-8017-088-8
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